Oldest Player: Darren Oliver (37)
Youngest Player: Nick Adenhart (21)
Longest Tenure: Robb Quinlan, Vladimir Guerrero, Garret Anderson, Juan Rivera, Maicer Izturis, John Lackey, Chone Figgins, Casey Kotchman, Jeff Mathis, Mike Napoli, Kendrys Morales, Erick Aybar, Howie Kendrick, Reggie Willits, Ervin Santana (3)
Top Hitter: Vladimir Guerrero (27)
Top Pitcher: Ervin Santana (3)
Top Draft Pick: Tyler Chatwood (#74)
Roster Continuity: 80.46%
Top Prospect: Brandon Wood
| 2008-03-31 | @ MIN | 1 | L 2-3 | 0-1 | 3 | 49,596 | Jered Weaver | Livan Hernandez | Livan Hernandez | Jered Weaver | Joe Nathan | 2 | 3 | -1 |
| 2008-04-01 | @ MIN | 2 | W 9-1 | 1-1 | 1 | 24,586 | Jon Garland | Boof Bonser | Jon Garland | Boof Bonser | | 11 | 4 | 7 |
| 2008-04-02 | @ MIN | 3 | W 1-0 | 2-1 | 1 | 21,932 | Joe Saunders | Nick Blackburn | Joe Saunders | Nick Blackburn | Francisco Rodriguez | 12 | 4 | 8 |
| 2008-04-03 | @ MIN | 4 | W 5-4 | 3-1 | 1 | 17,084 | Ervin Santana | Kevin Slowey | Ervin Santana | Kevin Slowey | Francisco Rodriguez | 17 | 8 | 9 |
| 2008-04-04 | vs TEX | 5 | L 6-11 | 3-2 | 1 | 43,838 | Dustin Moseley | Kason Gabbard | Kason Gabbard | Dustin Moseley | | 23 | 19 | 4 |
| 2008-04-05 | vs TEX | 6 | W 2-1 | 4-2 | 1 | 41,170 | Jered Weaver | Kevin Millwood | Jered Weaver | Kevin Millwood | Francisco Rodriguez | 25 | 20 | 5 |
| 2008-04-06 | vs TEX | 7 | L 4-10 | 4-3 | 1 | 39,242 | Jon Garland | Vicente Padilla | Vicente Padilla | Jon Garland | | 29 | 30 | -1 |
| 2008-04-07 | vs CLE | 8 | W 6-4 | 5-3 | 1 | 35,014 | Joe Saunders | Fausto Carmona | Scot Shields | Joe Borowski | | 35 | 34 | 1 |
| 2008-04-08 | vs CLE | 9 | L 3-4 | 5-4 | 1 | 37,587 | Ervin Santana | Jake Westbrook | Jake Westbrook | Justin Speier | | 38 | 38 | 0 |
| 2008-04-09 | vs CLE | 10 | W 9-5 | 6-4 | 1 | 36,168 | Dustin Moseley | Paul Byrd | Dustin Moseley | Paul Byrd | | 47 | 43 | 4 |
| 2008-04-11 | @ SEA | 11 | L 5-8 | 6-5 | 2 | 28,915 | Jered Weaver | Felix Hernandez | Felix Hernandez | Jered Weaver | Mark Lowe | 52 | 51 | 1 |
| 2008-04-12 | @ SEA | 12 | L 3-8 | 6-6 | 2 | 34,963 | Jon Garland | Carlos Silva | Carlos Silva | Jon Garland | | 55 | 59 | -4 |
| 2008-04-13 | @ SEA | 13 | W 10-5 | 7-6 | 2 | 30,664 | Joe Saunders | Cha-Seung Baek | Joe Saunders | Cha-Seung Baek | | 65 | 64 | 1 |
| 2008-04-14 | @ TEX | 14 | W 7-4 | 8-6 | 2 | 16,541 | Ervin Santana | Jason Jennings | Ervin Santana | Jason Jennings | Francisco Rodriguez | 72 | 68 | 4 |
| 2008-04-15 | @ TEX | 15 | W 7-4 | 9-6 | 1 | 15,595 | Dustin Moseley | Kevin Millwood | Darren Oliver | Josh Rupe | Francisco Rodriguez | 79 | 72 | 7 |
| 2008-04-16 | vs KCA | 16 | L 2-3 | 9-7 | 1 | 41,336 | Jered Weaver | Gil Meche | Gil Meche | Jered Weaver | Joakim Soria | 81 | 75 | 6 |
| 2008-04-17 | vs KCA | 17 | W 5-3 | 10-7 | 1 | 40,021 | Jon Garland | Brett Tomko | Jon Garland | Brett Tomko | Francisco Rodriguez | 86 | 78 | 8 |
| 2008-04-18 | vs SEA | 18 | W 5-4 | 11-7 | 1 | 43,939 | Joe Saunders | R.A. Dickey | Joe Saunders | R.A. Dickey | Francisco Rodriguez | 91 | 82 | 9 |
| 2008-04-19 | vs SEA | 19 | W 4-1 | 12-7 | 1 | 43,959 | Ervin Santana | Jarrod Washburn | Ervin Santana | Jarrod Washburn | Scot Shields | 95 | 83 | 12 |
| 2008-04-20 | vs SEA | 20 | L 2-4 | 12-8 | 1 | 43,631 | Dustin Moseley | Miguel Batista | Miguel Batista | Dustin Moseley | Ryan Rowland-Smith | 97 | 87 | 10 |
| 2008-04-22 | @ BOS | 21 | L 6-7 | 12-9 | 1 | 37,982 | Jered Weaver | David Pauley | Mike Timlin | Darren Oliver | Jonathan Papelbon | 103 | 94 | 9 |
| 2008-04-23 | @ BOS | 22 | W 6-4 | 13-9 | 1 | 38,172 | Jon Garland | Jon Lester | Jon Garland | Craig Hansen | Francisco Rodriguez | 109 | 98 | 11 |
| 2008-04-24 | @ BOS | 23 | W 7-5 | 14-9 | 1 | 37,848 | Joe Saunders | Justin Masterson | Joe Saunders | Manny Delcarmen | Francisco Rodriguez | 116 | 103 | 13 |
| 2008-04-25 | @ DET | 24 | W 4-3 | 15-9 | 1 | 40,380 | Ervin Santana | Nate Robertson | Ervin Santana | Nate Robertson | Francisco Rodriguez | 120 | 106 | 14 |
| 2008-04-26 | @ DET | 25 | L 4-6 | 15-10 | 1 | 42,068 | Dustin Moseley | Armando Galarraga | Aquilino Lopez | Darren O'Day | Todd Jones | 124 | 112 | 12 |
| 2008-04-27 | @ DET | 26 | W 6-2 | 16-10 | 1 | 36,347 | Jered Weaver | Justin Verlander | Jered Weaver | Justin Verlander | | 130 | 114 | 16 |
| 2008-04-28 | vs OAK | 27 | L 2-14 | 16-11 | 2 | 37,725 | Jon Garland | Chad Gaudin | Chad Gaudin | Jon Garland | | 132 | 128 | 4 |
| 2008-04-29 | vs OAK | 28 | W 2-0 | 17-11 | 1 | 35,764 | Joe Saunders | Greg Smith | Joe Saunders | Greg Smith | Francisco Rodriguez | 134 | 128 | 6 |
| 2008-04-30 | vs OAK | 29 | W 6-1 | 18-11 | 1 | 35,301 | Ervin Santana | Dana Eveland | Ervin Santana | Dana Eveland | | 140 | 129 | 11 |
| 2008-05-01 | vs OAK | 30 | L 8-15 | 18-12 | 1 | 37,396 | Nick Adenhart | Justin Duchscherer | Justin Duchscherer | Dustin Moseley | | 148 | 144 | 4 |
| 2008-05-02 | vs BAL | 31 | L 3-4 | 18-13 | 1 | 41,515 | Jered Weaver | Jeremy Guthrie | Jeremy Guthrie | Jered Weaver | George Sherrill | 151 | 148 | 3 |
| 2008-05-03 | vs BAL | 32 | W 3-1 | 19-13 | 1 | 37,601 | Jon Garland | Daniel Cabrera | Jon Garland | Daniel Cabrera | Francisco Rodriguez | 154 | 149 | 5 |
| 2008-05-04 | vs BAL | 33 | W 6-5 | 20-13 | 1 | 39,273 | Joe Saunders | Steve Trachsel | Joe Saunders | Steve Trachsel | Francisco Rodriguez | 160 | 154 | 6 |
| 2008-05-05 | @ KCA | 34 | W 4-0 | 21-13 | 1 | 12,157 | Ervin Santana | Brett Tomko | Ervin Santana | Ramon Ramirez | | 164 | 154 | 10 |
| 2008-05-06 | @ KCA | 35 | W 5-3 | 22-13 | 1 | 11,354 | Nick Adenhart | Brian Bannister | Darren Oliver | Brian Bannister | Francisco Rodriguez | 169 | 157 | 12 |
| 2008-05-07 | @ KCA | 36 | L 4-9 | 22-14 | 1 | 11,084 | Jered Weaver | Zack Greinke | Zack Greinke | Jered Weaver | | 173 | 166 | 7 |
| 2008-05-09 | @ TBA | 37 | L 0-2 | 22-15 | 1 | 12,039 | Jon Garland | James Shields | James Shields | Justin Speier | | 173 | 168 | 5 |
| 2008-05-10 | @ TBA | 38 | L 0-2 | 22-16 | 1 | 25,512 | Joe Saunders | Scott Kazmir | Scott Kazmir | Joe Saunders | Troy Percival | 173 | 170 | 3 |
| 2008-05-11 | @ TBA | 39 | L 5-8 | 22-17 | 2 | 13,010 | Ervin Santana | Andy Sonnanstine | J.P. Howell | Justin Speier | Troy Percival | 178 | 178 | 0 |
| 2008-05-12 | vs CHA | 40 | W 10-7 | 23-17 | 2 | 38,723 | Nick Adenhart | Mark Buehrle | Nick Adenhart | Mark Buehrle | Francisco Rodriguez | 188 | 185 | 3 |
| 2008-05-13 | vs CHA | 41 | W 2-0 | 24-17 | 1 | 35,333 | Jered Weaver | John Danks | Scot Shields | Octavio Dotel | Francisco Rodriguez | 190 | 185 | 5 |
| 2008-05-14 | vs CHA | 42 | L 1-6 | 24-18 | 1 | 37,059 | John Lackey | Jose Contreras | Jose Contreras | Scot Shields | | 191 | 191 | 0 |
| 2008-05-15 | vs CHA | 43 | L 3-4 | 24-19 | 1 | 41,444 | Jon Garland | Javier Vazquez | Octavio Dotel | Francisco Rodriguez | Bobby Jenks | 194 | 195 | -1 |
| 2008-05-16 | vs LAN | 44 | W 4-2 | 25-19 | 1 | 44,047 | Joe Saunders | Hiroki Kuroda | Joe Saunders | Hiroki Kuroda | Francisco Rodriguez | 198 | 197 | 1 |
| 2008-05-17 | vs LAN | 45 | L 3-6 | 25-20 | 1 | 43,906 | Ervin Santana | Chan Ho Park | Hong-Chih Kuo | Ervin Santana | | 201 | 203 | -2 |
| 2008-05-18 | vs LAN | 46 | W 10-2 | 26-20 | 1 | 44,007 | Jered Weaver | Derek Lowe | Jered Weaver | Derek Lowe | | 211 | 205 | 6 |
| 2008-05-20 | @ TOR | 47 | W 3-1 | 27-20 | 1 | 31,487 | John Lackey | Dustin McGowan | John Lackey | Dustin McGowan | Francisco Rodriguez | 214 | 206 | 8 |
| 2008-05-21 | @ TOR | 48 | W 4-3 | 28-20 | 1 | 20,163 | Jon Garland | Shaun Marcum | Jon Garland | Shaun Marcum | Francisco Rodriguez | 218 | 209 | 9 |
| 2008-05-22 | @ TOR | 49 | L 3-4 | 28-21 | 1 | 22,007 | Ervin Santana | A.J. Burnett | A.J. Burnett | Ervin Santana | B.J. Ryan | 221 | 213 | 8 |
| 2008-05-23 | @ CHA | 50 | W 3-1 | 29-21 | 1 | 28,156 | Joe Saunders | Gavin Floyd | Joe Saunders | Gavin Floyd | Francisco Rodriguez | 224 | 214 | 10 |
| 2008-05-24 | @ CHA | 51 | W 2-0 | 30-21 | 1 | 38,434 | Jered Weaver | John Danks | Jered Weaver | John Danks | Francisco Rodriguez | 226 | 214 | 12 |
| 2008-05-25 | @ CHA | 52 | L 2-3 | 30-22 | 1 | 36,195 | John Lackey | Jose Contreras | Scott Linebrink | John Lackey | | 228 | 217 | 11 |
| 2008-05-26 | vs DET | 53 | W 1-0 | 31-22 | 1 | 41,031 | Jon Garland | Kenny Rogers | Jose Arredondo | Freddy Dolsi | | 229 | 217 | 12 |
| 2008-05-27 | vs DET | 54 | W 3-2 | 32-22 | 1 | 36,569 | Ervin Santana | Jeremy Bonderman | Ervin Santana | Aquilino Lopez | | 232 | 219 | 13 |
| 2008-05-28 | vs DET | 55 | L 2-6 | 32-23 | 1 | 42,191 | Joe Saunders | Armando Galarraga | Armando Galarraga | Joe Saunders | | 234 | 225 | 9 |
| 2008-05-30 | vs TOR | 56 | L 4-10 | 32-24 | 1 | 42,577 | Jered Weaver | Dustin McGowan | Dustin McGowan | Jered Weaver | | 238 | 235 | 3 |
| 2008-05-31 | vs TOR | 57 | W 3-2 | 33-24 | 1 | 43,645 | John Lackey | Shaun Marcum | Scot Shields | Brian Tallet | | 241 | 237 | 4 |
| 2008-06-01 | vs TOR | 58 | W 4-3 | 34-24 | 1 | 40,026 | Jon Garland | A.J. Burnett | Jose Arredondo | B.J. Ryan | | 245 | 240 | 5 |
| 2008-06-02 | @ SEA | 59 | W 4-2 | 35-24 | 1 | 22,110 | Ervin Santana | Jarrod Washburn | Ervin Santana | Jarrod Washburn | Francisco Rodriguez | 249 | 242 | 7 |
| 2008-06-03 | @ SEA | 60 | W 5-4 | 36-24 | 1 | 23,534 | Joe Saunders | Erik Bedard | Joe Saunders | Erik Bedard | Francisco Rodriguez | 254 | 246 | 8 |
| 2008-06-04 | @ SEA | 61 | W 5-4 | 37-24 | 1 | 32,774 | Jered Weaver | Carlos Silva | Jered Weaver | Carlos Silva | Francisco Rodriguez | 259 | 250 | 9 |
| 2008-06-06 | @ OAK | 62 | W 3-1 | 38-24 | 1 | 25,120 | John Lackey | Joe Blanton | John Lackey | Joe Blanton | Francisco Rodriguez | 262 | 251 | 11 |
| 2008-06-07 | @ OAK | 63 | W 5-3 | 39-24 | 1 | 29,294 | Jon Garland | Greg Smith | Jon Garland | Greg Smith | Francisco Rodriguez | 267 | 254 | 13 |
| 2008-06-08 | @ OAK | 64 | L 3-7 | 39-25 | 1 | 26,332 | Ervin Santana | Rich Harden | Brad Ziegler | Chris Bootcheck | | 270 | 261 | 9 |
| 2008-06-09 | vs TBA | 65 | L 4-13 | 39-26 | 1 | 42,019 | Joe Saunders | Edwin Jackson | Edwin Jackson | Joe Saunders | | 274 | 274 | 0 |
| 2008-06-10 | vs TBA | 66 | W 6-1 | 40-26 | 1 | 37,610 | Jered Weaver | James Shields | Jered Weaver | James Shields | | 280 | 275 | 5 |
| 2008-06-11 | vs TBA | 67 | W 4-2 | 41-26 | 1 | 36,622 | John Lackey | Scott Kazmir | John Lackey | Scott Kazmir | Francisco Rodriguez | 284 | 277 | 7 |
| 2008-06-13 | vs ATL | 68 | L 2-5 | 41-27 | 1 | 43,919 | Jon Garland | Jo-Jo Reyes | Jo-Jo Reyes | Jon Garland | Jeff Bennett | 286 | 282 | 4 |
| 2008-06-14 | vs ATL | 69 | L 4-9 | 41-28 | 1 | 43,894 | Ervin Santana | Charlie Morton | Charlie Morton | Ervin Santana | | 290 | 291 | -1 |
| 2008-06-15 | vs ATL | 70 | W 2-0 | 42-28 | 1 | 43,723 | Joe Saunders | Jorge Campillo | Joe Saunders | Jorge Campillo | Francisco Rodriguez | 292 | 291 | 1 |
| 2008-06-16 | vs NYN | 71 | L 6-9 | 42-29 | 1 | 39,229 | Jered Weaver | Mike Pelfrey | Mike Pelfrey | Jered Weaver | Billy Wagner | 298 | 300 | -2 |
| 2008-06-17 | vs NYN | 72 | W 6-1 | 43-29 | 1 | 40,122 | John Lackey | Johan Santana | John Lackey | Johan Santana | Scot Shields | 304 | 301 | 3 |
| 2008-06-18 | vs NYN | 73 | L 4-5 | 43-30 | 1 | 43,138 | Jon Garland | Oliver Perez | Duaner Sanchez | Justin Speier | Billy Wagner | 308 | 306 | 2 |
| 2008-06-20 | @ PHI | 74 | W 7-1 | 44-30 | 1 | 45,033 | Ervin Santana | Adam Eaton | Ervin Santana | Adam Eaton | | 315 | 307 | 8 |
| 2008-06-21 | @ PHI | 75 | W 6-2 | 45-30 | 1 | 45,196 | Joe Saunders | Brett Myers | Joe Saunders | Brett Myers | Francisco Rodriguez | 321 | 309 | 12 |
| 2008-06-22 | @ PHI | 76 | W 3-2 | 46-30 | 1 | 44,571 | Jered Weaver | Cole Hamels | Jered Weaver | Cole Hamels | Francisco Rodriguez | 324 | 311 | 13 |
| 2008-06-23 | @ WAS | 77 | W 3-2 | 47-30 | 1 | 24,805 | John Lackey | Jason Bergmann | John Lackey | Saul Rivera | Francisco Rodriguez | 327 | 313 | 14 |
| 2008-06-24 | @ WAS | 78 | W 8-3 | 48-30 | 1 | 28,531 | Jon Garland | Shawn Hill | Jon Garland | Shawn Hill | | 335 | 316 | 19 |
| 2008-06-25 | @ WAS | 79 | L 4-5 | 48-31 | 1 | 29,180 | Ervin Santana | Tim Redding | Jon Rauch | Scot Shields | | 339 | 321 | 18 |
| 2008-06-27 | @ LAN | 80 | L 0-6 | 48-32 | 1 | 50,419 | Joe Saunders | Chan Ho Park | Chan Ho Park | Joe Saunders | | 339 | 327 | 12 |
| 2008-06-28 | @ LAN | 81 | L 0-1 | 48-33 | 1 | 55,784 | Jered Weaver | Chad Billingsley | Chad Billingsley | Jered Weaver | Takashi Saito | 339 | 328 | 11 |
| 2008-06-29 | @ LAN | 82 | W 1-0 | 49-33 | 1 | 48,155 | John Lackey | Derek Lowe | John Lackey | Derek Lowe | Francisco Rodriguez | 340 | 328 | 12 |
| 2008-06-30 | vs OAK | 83 | L 1-6 | 49-34 | 1 | 42,046 | Jon Garland | Greg Smith | Greg Smith | Jon Garland | | 341 | 334 | 7 |
| 2008-07-01 | vs OAK | 84 | W 5-3 | 50-34 | 1 | 42,047 | Ervin Santana | Rich Harden | Scot Shields | Alan Embree | Francisco Rodriguez | 346 | 337 | 9 |
| 2008-07-02 | vs OAK | 85 | W 7-4 | 51-34 | 1 | 41,091 | Joe Saunders | Dana Eveland | Joe Saunders | Keith Foulke | Francisco Rodriguez | 353 | 341 | 12 |
| 2008-07-04 | vs TOR | 86 | W 8-2 | 52-34 | 1 | 44,021 | Jered Weaver | A.J. Burnett | Jered Weaver | A.J. Burnett | | 361 | 343 | 18 |
| 2008-07-05 | vs TOR | 87 | L 5-7 | 52-35 | 1 | 43,767 | John Lackey | Roy Halladay | Roy Halladay | John Lackey | | 366 | 350 | 16 |
| 2008-07-06 | vs TOR | 88 | W 7-1 | 53-35 | 1 | 41,026 | Jon Garland | Jesse Litsch | Jon Garland | Jesse Litsch | | 373 | 351 | 22 |
| 2008-07-07 | @ TEX | 89 | W 9-6 | 54-35 | 1 | 21,170 | Ervin Santana | Luis Mendoza | Ervin Santana | Luis Mendoza | Francisco Rodriguez | 382 | 357 | 25 |
| 2008-07-08 | @ TEX | 90 | L 2-3 | 54-36 | 1 | 18,788 | Joe Saunders | Matt Harrison | Matt Harrison | Joe Saunders | C.J. Wilson | 384 | 360 | 24 |
| 2008-07-09 | @ TEX | 91 | L 4-5 | 54-37 | 1 | 24,515 | Jered Weaver | Warner Madrigal | Jamey Wright | Francisco Rodriguez | | 388 | 365 | 23 |
| 2008-07-10 | @ TEX | 92 | W 11-10 | 55-37 | 1 | 23,262 | John Lackey | Scott Feldman | Justin Speier | Jamey Wright | Francisco Rodriguez | 399 | 375 | 24 |
| 2008-07-11 | @ OAK | 93 | L 2-9 | 55-38 | 1 | 31,372 | Jon Garland | Sean Gallagher | Sean Gallagher | Jon Garland | | 401 | 384 | 17 |
| 2008-07-12 | @ OAK | 94 | W 4-1 | 56-38 | 1 | 27,161 | Ervin Santana | Dana Eveland | Ervin Santana | Dana Eveland | Francisco Rodriguez | 405 | 385 | 20 |
| 2008-07-13 | @ OAK | 95 | W 4-3 | 57-38 | 1 | 29,352 | Dustin Moseley | Justin Duchscherer | Jose Arredondo | Huston Street | Francisco Rodriguez | 409 | 388 | 21 |
| 2008-07-18 | vs BOS | 96 | W 11-3 | 58-38 | 1 | 44,260 | John Lackey | Clay Buchholz | John Lackey | Clay Buchholz | | 420 | 391 | 29 |
| 2008-07-19 | vs BOS | 97 | W 4-2 | 59-38 | 1 | 44,005 | Joe Saunders | Josh Beckett | Jose Arredondo | Josh Beckett | Francisco Rodriguez | 424 | 393 | 31 |
| 2008-07-20 | vs BOS | 98 | W 5-3 | 60-38 | 1 | 44,164 | Jon Garland | Tim Wakefield | Darren Oliver | Tim Wakefield | Francisco Rodriguez | 429 | 396 | 33 |
| 2008-07-21 | vs CLE | 99 | L 2-5 | 60-39 | 1 | 43,037 | Ervin Santana | Paul Byrd | Paul Byrd | Ervin Santana | Masahide Kobayashi | 431 | 401 | 30 |
| 2008-07-22 | vs CLE | 100 | W 3-2 | 61-39 | 1 | 43,505 | Jered Weaver | Matt Ginter | Darren Oliver | Matt Ginter | Francisco Rodriguez | 434 | 403 | 31 |
| 2008-07-23 | vs CLE | 101 | W 14-11 | 62-39 | 1 | 42,187 | John Lackey | Aaron Laffey | John Lackey | Aaron Laffey | Francisco Rodriguez | 448 | 414 | 34 |
| 2008-07-25 | @ BAL | 102 | W 6-5 | 63-39 | 1 | 27,999 | Joe Saunders | Brian Burres | Joe Saunders | Brian Burres | Francisco Rodriguez | 454 | 419 | 35 |
| 2008-07-26 | @ BAL | 103 | W 11-6 | 64-39 | 1 | 21,819 | Jon Garland | Radhames Liz | Jon Garland | Radhames Liz | | 465 | 425 | 40 |
| 2008-07-27 | @ BAL | 104 | L 2-5 | 64-40 | 1 | 23,365 | Ervin Santana | Garrett Olson | Garrett Olson | Ervin Santana | George Sherrill | 467 | 430 | 37 |
| 2008-07-28 | @ BOS | 105 | W 7-5 | 65-40 | 1 | 37,830 | Jered Weaver | Daisuke Matsuzaka | Jered Weaver | Daisuke Matsuzaka | Francisco Rodriguez | 474 | 435 | 39 |
| 2008-07-29 | @ BOS | 106 | W 6-2 | 66-40 | 1 | 38,110 | John Lackey | Clay Buchholz | John Lackey | Clay Buchholz | | 480 | 437 | 43 |
| 2008-07-30 | @ BOS | 107 | W 9-2 | 67-40 | 1 | 38,042 | Joe Saunders | Josh Beckett | Joe Saunders | Josh Beckett | | 489 | 439 | 50 |
| 2008-07-31 | @ NYA | 108 | W 12-6 | 68-40 | 1 | 53,405 | Jon Garland | Andy Pettitte | Jon Garland | Andy Pettitte | | 501 | 445 | 56 |
| 2008-08-01 | @ NYA | 109 | W 1-0 | 69-40 | 1 | 53,997 | Ervin Santana | Sidney Ponson | Ervin Santana | Mariano Rivera | Francisco Rodriguez | 502 | 445 | 57 |
| 2008-08-02 | @ NYA | 110 | L 2-8 | 69-41 | 1 | 54,170 | Jered Weaver | Mike Mussina | Mike Mussina | Jered Weaver | | 504 | 453 | 51 |
| 2008-08-03 | @ NYA | 111 | L 9-14 | 69-42 | 1 | 54,204 | John Lackey | Darrell Rasner | Edwar Ramirez | Scot Shields | | 513 | 467 | 46 |
| 2008-08-04 | vs BAL | 112 | W 6-5 | 70-42 | 1 | 41,902 | Joe Saunders | Dennis Sarfate | Francisco Rodriguez | George Sherrill | | 519 | 472 | 47 |
| 2008-08-05 | vs BAL | 113 | L 0-3 | 70-43 | 1 | 44,027 | Jon Garland | Chris Waters | Chris Waters | Jon Garland | George Sherrill | 519 | 475 | 44 |
| 2008-08-06 | vs BAL | 114 | W 9-4 | 71-43 | 1 | 40,130 | Ervin Santana | Garrett Olson | Ervin Santana | Garrett Olson | | 528 | 479 | 49 |
| 2008-08-08 | vs NYA | 115 | W 10-5 | 72-43 | 1 | 44,158 | Jered Weaver | Ian Kennedy | Jered Weaver | Ian Kennedy | | 538 | 484 | 54 |
| 2008-08-09 | vs NYA | 116 | W 11-4 | 73-43 | 1 | 43,919 | John Lackey | Dan Giese | Scot Shields | Edwar Ramirez | | 549 | 488 | 61 |
| 2008-08-10 | vs NYA | 117 | W 4-3 | 74-43 | 1 | 44,138 | Joe Saunders | Andy Pettitte | Francisco Rodriguez | Damaso Marte | | 553 | 491 | 62 |
| 2008-08-12 | vs SEA | 118 | W 7-3 | 75-43 | 1 | 42,086 | Jon Garland | Jarrod Washburn | Jon Garland | Jarrod Washburn | Francisco Rodriguez | 560 | 494 | 66 |
| 2008-08-13 | vs SEA | 119 | L 7-10 | 75-44 | 1 | 42,754 | Ervin Santana | Felix Hernandez | Roy Corcoran | Justin Speier | | 567 | 504 | 63 |
| 2008-08-15 | @ CLE | 120 | L 2-3 | 75-45 | 1 | 30,962 | Jered Weaver | Cliff Lee | Cliff Lee | Jose Arredondo | | 569 | 507 | 62 |
| 2008-08-16 | @ CLE | 121 | W 4-3 | 76-45 | 1 | 33,051 | John Lackey | Fausto Carmona | John Lackey | Fausto Carmona | Francisco Rodriguez | 573 | 510 | 63 |
| 2008-08-17 | @ CLE | 122 | L 3-4 | 76-46 | 1 | 28,356 | Joe Saunders | Jeremy Sowers | Jeremy Sowers | Justin Speier | Jensen Lewis | 576 | 514 | 62 |
| 2008-08-18 | @ TBA | 123 | L 4-6 | 76-47 | 1 | 15,896 | Jon Garland | Andy Sonnanstine | Andy Sonnanstine | Jon Garland | Dan Wheeler | 580 | 520 | 60 |
| 2008-08-19 | @ TBA | 124 | L 2-4 | 76-48 | 1 | 15,902 | Ervin Santana | James Shields | James Shields | Scot Shields | Dan Wheeler | 582 | 524 | 58 |
| 2008-08-20 | @ TBA | 125 | W 5-4 | 77-48 | 1 | 19,157 | Jered Weaver | Matt Garza | Jose Arredondo | Grant Balfour | Francisco Rodriguez | 587 | 528 | 59 |
| 2008-08-21 | vs MIN | 126 | L 1-2 | 77-49 | 1 | 41,367 | John Lackey | Scott Baker | Jesse Crain | Justin Speier | Joe Nathan | 588 | 530 | 58 |
| 2008-08-22 | vs MIN | 127 | L 0-9 | 77-50 | 1 | 43,819 | Joe Saunders | Glen Perkins | Glen Perkins | Joe Saunders | | 588 | 539 | 49 |
| 2008-08-23 | vs MIN | 128 | W 7-5 | 78-50 | 1 | 43,906 | Jon Garland | Nick Blackburn | Darren Oliver | Nick Blackburn | Francisco Rodriguez | 595 | 544 | 51 |
| 2008-08-24 | vs MIN | 129 | W 5-3 | 79-50 | 1 | 40,011 | Ervin Santana | Kevin Slowey | Jose Arredondo | Jesse Crain | Francisco Rodriguez | 600 | 547 | 53 |
| 2008-08-25 | vs OAK | 130 | L 1-2 | 79-51 | 1 | 39,584 | Jered Weaver | Dallas Braden | Dallas Braden | Jered Weaver | Brad Ziegler | 601 | 549 | 52 |
| 2008-08-26 | vs OAK | 131 | W 5-1 | 80-51 | 1 | 37,431 | John Lackey | Greg Smith | John Lackey | Greg Smith | | 606 | 550 | 56 |
| 2008-08-27 | vs OAK | 132 | L 5-6 | 80-52 | 1 | 38,587 | Joe Saunders | Gio Gonzalez | Huston Street | Joe Saunders | Brad Ziegler | 611 | 556 | 55 |
| 2008-08-28 | vs TEX | 133 | W 7-5 | 81-52 | 1 | 37,541 | Jon Garland | Brandon McCarthy | Jon Garland | Jamey Wright | Francisco Rodriguez | 618 | 561 | 57 |
| 2008-08-29 | vs TEX | 134 | W 3-1 | 82-52 | 1 | 40,084 | Ervin Santana | Dustin Nippert | Ervin Santana | Dustin Nippert | Francisco Rodriguez | 621 | 562 | 59 |
| 2008-08-30 | vs TEX | 135 | W 4-3 | 83-52 | 1 | 43,937 | Jered Weaver | Scott Feldman | Jose Arredondo | Scott Feldman | Francisco Rodriguez | 625 | 565 | 60 |
| 2008-08-31 | vs TEX | 136 | L 3-4 | 83-53 | 1 | 39,153 | John Lackey | Kevin Millwood | Kevin Millwood | John Lackey | Frank Francisco | 628 | 569 | 59 |
| 2008-09-02 | @ DET | 137 | W 5-4 | 84-53 | 1 | 35,320 | Joe Saunders | Chris Lambert | Scot Shields | Fernando Rodney | Francisco Rodriguez | 633 | 573 | 60 |
| 2008-09-03 | @ DET | 138 | L 6-9 | 84-54 | 1 | 36,671 | Jon Garland | Zach Miner | Kyle Farnsworth | Jose Arredondo | Fernando Rodney | 639 | 582 | 57 |
| 2008-09-04 | @ DET | 139 | W 7-1 | 85-54 | 1 | 37,890 | Ervin Santana | Kenny Rogers | Ervin Santana | Kenny Rogers | | 646 | 583 | 63 |
| 2008-09-05 | @ CHA | 140 | L 2-10 | 85-55 | 1 | 32,502 | Dustin Moseley | Mark Buehrle | Mark Buehrle | Dustin Moseley | | 648 | 593 | 55 |
| 2008-09-06 | @ CHA | 141 | L 6-7 | 85-56 | 1 | 31,046 | John Lackey | Gavin Floyd | Ehren Wassermann | Justin Speier | | 654 | 600 | 54 |
| 2008-09-07 | @ CHA | 142 | W 3-2 | 86-56 | 1 | 26,029 | Joe Saunders | John Danks | Joe Saunders | Horacio Ramirez | Francisco Rodriguez | 657 | 602 | 55 |
| 2008-09-08 | vs NYA | 143 | W 12-1 | 87-56 | 1 | 41,025 | Jon Garland | Carl Pavano | Jon Garland | Carl Pavano | | 669 | 603 | 66 |
| 2008-09-09 | vs NYA | 144 | L 1-7 | 87-57 | 1 | 43,042 | Ervin Santana | Alfredo Aceves | Alfredo Aceves | Ervin Santana | | 670 | 610 | 60 |
| 2008-09-10 | vs NYA | 145 | W 4-2 | 88-57 | 1 | 39,783 | Dustin Moseley | Andy Pettitte | Dustin Moseley | Andy Pettitte | Francisco Rodriguez | 674 | 612 | 62 |
| 2008-09-11 | vs SEA | 146 | W 7-4 | 89-57 | 1 | 38,205 | Jered Weaver | Brandon Morrow | Jered Weaver | Brandon Morrow | Francisco Rodriguez | 681 | 616 | 65 |
| 2008-09-12 | vs SEA | 147 | W 5-3 | 90-57 | 1 | 43,743 | Joe Saunders | Ryan Rowland-Smith | Jose Arredondo | Miguel Batista | | 686 | 619 | 67 |
| 2008-09-13 | vs SEA | 148 | W 5-2 | 91-57 | 1 | 43,757 | Jon Garland | Ryan Feierabend | Jon Garland | Ryan Feierabend | Francisco Rodriguez | 691 | 621 | 70 |
| 2008-09-14 | vs SEA | 149 | W 4-3 | 92-57 | 1 | 41,528 | Ervin Santana | Felix Hernandez | Jose Arredondo | Roy Corcoran | | 695 | 624 | 71 |
| 2008-09-16 | @ OAK | 150 | L 1-8 | 92-58 | 1 | 14,325 | John Lackey | Sean Gallagher | Sean Gallagher | John Lackey | | 696 | 632 | 64 |
| 2008-09-17 | @ OAK | 151 | L 2-3 | 92-59 | 1 | 20,102 | Jered Weaver | Greg Smith | Brad Ziegler | Francisco Rodriguez | | 698 | 635 | 63 |
| 2008-09-18 | @ OAK | 152 | W 6-4 | 93-59 | 1 | 12,645 | Joe Saunders | Josh Outman | Joe Saunders | Josh Outman | Francisco Rodriguez | 704 | 639 | 65 |
| 2008-09-19 | @ TEX | 153 | W 15-13 | 94-59 | 1 | 23,708 | Jon Garland | Matt Harrison | Darren Oliver | Jamey Wright | Scot Shields | 719 | 652 | 67 |
| 2008-09-20 | @ TEX | 154 | W 7-3 | 95-59 | 1 | 38,973 | Dustin Moseley | Vicente Padilla | Justin Speier | Vicente Padilla | Francisco Rodriguez | 726 | 655 | 71 |
| 2008-09-21 | @ TEX | 155 | W 7-3 | 96-59 | 1 | 28,390 | John Lackey | Scott Feldman | John Lackey | Scott Feldman | | 733 | 658 | 75 |
| 2008-09-22 | @ SEA | 156 | W 2-1 | 97-59 | 1 | 19,717 | Ervin Santana | Ryan Rowland-Smith | Ervin Santana | Ryan Rowland-Smith | Francisco Rodriguez | 735 | 659 | 76 |
| 2008-09-23 | @ SEA | 157 | L 6-9 | 97-60 | 1 | 19,065 | Jered Weaver | Ryan Feierabend | Roy Corcoran | Kevin Jepsen | J.J. Putz | 741 | 668 | 73 |
| 2008-09-24 | @ SEA | 158 | W 6-5 | 98-60 | 1 | 19,015 | Jon Garland | Felix Hernandez | Darren Oliver | Mark Lowe | Francisco Rodriguez | 747 | 673 | 74 |
| 2008-09-25 | @ SEA | 159 | W 6-4 | 99-60 | 1 | 16,939 | Dustin Moseley | Cesar Jimenez | Jose Arredondo | J.J. Putz | Scot Shields | 753 | 677 | 76 |
| 2008-09-26 | vs TEX | 160 | L 1-12 | 99-61 | 1 | 43,758 | John Lackey | Vicente Padilla | Vicente Padilla | John Lackey | | 754 | 689 | 65 |
| 2008-09-27 | vs TEX | 161 | L 4-8 | 99-62 | 1 | 43,141 | Ervin Santana | Scott Feldman | Scott Feldman | Ervin Santana | | 758 | 697 | 61 |
| 2008-09-28 | vs TEX | 162 | W 7-0 | 100-62 | 1 | 43,761 | Joe Saunders | Kevin Millwood | Joe Saunders | Kevin Millwood | | 765 | 697 | 68 |