| 2000-04-03 | @ TEX | 1 | L 4-10 | 0-1 | 3 | 49,332 | Mike Sirotka | Kenny Rogers | Kenny Rogers | Mike Sirotka | | 4 | 10 | -6 |
| 2000-04-04 | @ TEX | 2 | L 8-12 | 0-2 | 4 | 29,418 | Kip Wells | Rick Helling | Francisco Cordero | Bill Simas | | 12 | 22 | -10 |
| 2000-04-05 | @ TEX | 3 | W 12-8 | 1-2 | 3 | 25,544 | Jim Parque | Darren Oliver | Keith Foulke | Jeff Zimmerman | | 24 | 30 | -6 |
| 2000-04-06 | @ TEX | 4 | W 6-2 | 2-2 | 1 | 28,466 | James Baldwin | Esteban Loaiza | James Baldwin | Esteban Loaiza | | 30 | 32 | -2 |
| 2000-04-07 | @ OAK | 5 | W 7-6 | 3-2 | 1 | 10,549 | Cal Eldred | Gil Heredia | Scott Eyre | Mike Magnante | Keith Foulke | 37 | 38 | -1 |
| 2000-04-08 | @ OAK | 6 | W 7-3 | 4-2 | 1 | 13,125 | Mike Sirotka | Ron Mahay | Mike Sirotka | Ron Mahay | | 44 | 41 | 3 |
| 2000-04-09 | @ OAK | 7 | L 2-14 | 4-3 | 2 | 13,280 | Kip Wells | Kevin Appier | Kevin Appier | Kip Wells | | 46 | 55 | -9 |
| 2000-04-11 | @ TBA | 8 | W 13-6 | 5-3 | 3 | 13,639 | Jim Parque | Esteban Yan | Jim Parque | Esteban Yan | | 59 | 61 | -2 |
| 2000-04-12 | @ TBA | 9 | W 7-1 | 6-3 | 3 | 14,034 | James Baldwin | Dan Wheeler | James Baldwin | Dan Wheeler | | 66 | 62 | 4 |
| 2000-04-13 | @ TBA | 10 | L 5-6 | 6-4 | 3 | 15,464 | Cal Eldred | Steve Trachsel | Jim Mecir | Tanyon Sturtze | | 71 | 68 | 3 |
| 2000-04-14 | vs ANA | 11 | W 9-4 | 7-4 | 3 | 38,912 | Mike Sirotka | Ken Hill | Mike Sirotka | Ken Hill | | 80 | 72 | 8 |
| 2000-04-15 | vs ANA | 12 | L 1-3 | 7-5 | 3 | 14,135 | Kip Wells | Kent Bottenfield | Kent Bottenfield | Kip Wells | Troy Percival | 81 | 75 | 6 |
| 2000-04-16 | vs ANA | 13 | L 1-3 | 7-6 | 3 | 10,929 | Jim Parque | Scott Schoeneweis | Scott Schoeneweis | Jim Parque | Troy Percival | 82 | 78 | 4 |
| 2000-04-18 | vs SEA | 14 | W 18-11 | 8-6 | 2 | 9,898 | Cal Eldred | Aaron Sele | Tanyon Sturtze | Aaron Sele | | 100 | 89 | 11 |
| 2000-04-19 | vs SEA | 15 | W 5-2 | 9-6 | 1 | 8,425 | Scott Eyre | Gil Meche | Sean Lowe | Gil Meche | Bob Howry | 105 | 91 | 14 |
| 2000-04-21 | vs DET | 16 | W 7-2 | 10-6 | 1 | 11,278 | Kip Wells | C.J. Nitkowski | Kip Wells | C.J. Nitkowski | | 112 | 93 | 19 |
| 2000-04-22 | vs DET | 17 | W 14-6 | 11-6 | 1 | 16,410 | Jim Parque | Jeff Weaver | Jim Parque | Jeff Weaver | | 126 | 99 | 27 |
| 2000-04-23 | vs DET | 18 | W 9-4 | 12-6 | 1 | 12,154 | James Baldwin | Dave Borkowski | James Baldwin | Dave Borkowski | | 135 | 103 | 32 |
| 2000-04-24 | vs BAL | 19 | W 8-2 | 13-6 | 1 | 15,461 | Cal Eldred | Mike Mussina | Cal Eldred | Mike Mussina | | 143 | 105 | 38 |
| 2000-04-25 | vs BAL | 20 | L 6-12 | 13-7 | 1 | 11,658 | Mike Sirotka | Pat Rapp | Pat Rapp | Mike Sirotka | | 149 | 117 | 32 |
| 2000-04-26 | vs BAL | 21 | W 11-6 | 14-7 | 1 | 13,649 | Kip Wells | Sidney Ponson | Kip Wells | Sidney Ponson | | 160 | 123 | 37 |
| 2000-04-27 | vs BAL | 22 | W 13-4 | 15-7 | 1 | 13,225 | Jim Parque | Jose Mercedes | Jim Parque | Jose Mercedes | | 173 | 127 | 46 |
| 2000-04-28 | @ DET | 23 | W 3-2 | 16-7 | 1 | 26,916 | James Baldwin | Jeff Weaver | James Baldwin | Jeff Weaver | Keith Foulke | 176 | 129 | 47 |
| 2000-04-29 | @ DET | 24 | W 2-1 | 17-7 | 1 | 28,393 | Cal Eldred | Dave Mlicki | Cal Eldred | Dave Mlicki | Keith Foulke | 178 | 130 | 48 |
| 2000-04-30 | @ DET | 25 | L 3-4 | 17-8 | 1 | 28,435 | Mike Sirotka | Hideo Nomo | Matt Anderson | Scott Eyre | | 181 | 134 | 47 |
| 2000-05-01 | vs TOR | 26 | L 3-5 | 17-9 | 1 | 14,448 | Kip Wells | Chris Carpenter | Chris Carpenter | Kip Wells | Billy Koch | 184 | 139 | 45 |
| 2000-05-02 | vs TOR | 27 | L 1-4 | 17-10 | 1 | 10,397 | Jim Parque | Frank Castillo | Frank Castillo | Kelly Wunsch | Billy Koch | 185 | 143 | 42 |
| 2000-05-03 | vs TOR | 28 | W 7-3 | 18-10 | 1 | 12,026 | James Baldwin | Kelvim Escobar | James Baldwin | Kelvim Escobar | Keith Foulke | 192 | 146 | 46 |
| 2000-05-05 | @ KCA | 29 | L 1-5 | 18-11 | 1 | 19,622 | Cal Eldred | Chris Fussell | Chris Fussell | Cal Eldred | | 193 | 151 | 42 |
| 2000-05-06 | @ KCA | 30 | L 5-11 | 18-12 | 1 | 28,300 | Mike Sirotka | Chad Durbin | Jerry Spradlin | Mike Sirotka | | 198 | 162 | 36 |
| 2000-05-07 | @ KCA | 31 | L 8-12 | 18-13 | 1 | 23,107 | Kip Wells | Miguel Batista | Ricky Bottalico | Kelly Wunsch | | 206 | 174 | 32 |
| 2000-05-08 | @ BOS | 32 | L 2-3 | 18-14 | 1 | 23,468 | Tanyon Sturtze | Brian Rose | Brian Rose | Tanyon Sturtze | Derek Lowe | 208 | 177 | 31 |
| 2000-05-09 | @ BOS | 33 | W 6-0 | 19-14 | 1 | 25,371 | James Baldwin | Pete Schourek | James Baldwin | Pete Schourek | | 214 | 177 | 37 |
| 2000-05-10 | @ BOS | 34 | L 3-5 | 19-15 | 1 | 28,911 | Cal Eldred | Ramon Martinez | Ramon Martinez | Cal Eldred | Rich Garces | 217 | 182 | 35 |
| 2000-05-12 | vs MIN | 35 | L 3-4 | 19-16 | 2 | 12,526 | Jim Parque | Joe Mays | Travis Miller | Sean Lowe | Hector Carrasco | 220 | 186 | 34 |
| 2000-05-13 | vs MIN | 36 | W 4-3 | 20-16 | 2 | 22,545 | Mike Sirotka | Mark Redman | Kelly Wunsch | Bob Wells | | 224 | 189 | 35 |
| 2000-05-14 | vs MIN | 37 | W 5-3 | 21-16 | 1 | 29,177 | James Baldwin | Brad Radke | Kelly Wunsch | Brad Radke | Keith Foulke | 229 | 192 | 37 |
| 2000-05-16 | @ NYA | 38 | W 4-0 | 22-16 | 1 | 31,143 | Cal Eldred | Orlando Hernandez | Cal Eldred | Orlando Hernandez | | 233 | 192 | 41 |
| 2000-05-17 | @ NYA | 39 | L 4-9 | 22-17 | 2 | 26,887 | Jim Parque | Roger Clemens | Roger Clemens | Jim Parque | | 237 | 201 | 36 |
| 2000-05-19 | @ TOR | 40 | W 5-3 | 23-17 | 1 | 18,268 | Mike Sirotka | Kelvim Escobar | Mike Sirotka | Kelvim Escobar | Keith Foulke | 242 | 204 | 38 |
| 2000-05-20 | @ TOR | 41 | W 6-2 | 24-17 | 1 | 20,091 | James Baldwin | David Wells | James Baldwin | David Wells | | 248 | 206 | 42 |
| 2000-05-21 | @ TOR | 42 | W 2-1 | 25-17 | 1 | 18,264 | Cal Eldred | Frank Castillo | Cal Eldred | Frank Castillo | Keith Foulke | 250 | 207 | 43 |
| 2000-05-22 | @ TOR | 43 | L 3-4 | 25-18 | 1 | 19,167 | Jim Parque | Peter Munro | Billy Koch | Bob Howry | | 253 | 211 | 42 |
| 2000-05-23 | vs NYA | 44 | W 8-2 | 26-18 | 1 | 21,863 | Kip Wells | Roger Clemens | Kip Wells | Roger Clemens | | 261 | 213 | 48 |
| 2000-05-24 | vs NYA | 45 | L 4-12 | 26-19 | 1 | 23,144 | Mike Sirotka | Andy Pettitte | Andy Pettitte | Mike Sirotka | | 265 | 225 | 40 |
| 2000-05-25 | vs NYA | 46 | L 0-7 | 26-20 | 1 | 23,636 | James Baldwin | Ramiro Mendoza | Ramiro Mendoza | James Baldwin | | 265 | 232 | 33 |
| 2000-05-26 | vs CLE | 47 | W 5-3 | 27-20 | 1 | 18,225 | Cal Eldred | Chuck Finley | Cal Eldred | Chuck Finley | Keith Foulke | 270 | 235 | 35 |
| 2000-05-27 | vs CLE | 48 | W 14-3 | 28-20 | 1 | 30,250 | Jim Parque | Jaret Wright | Jim Parque | Jaret Wright | | 284 | 238 | 46 |
| 2000-05-28 | vs CLE | 49 | L 3-12 | 28-21 | 1 | 24,192 | Kip Wells | Bartolo Colon | Bartolo Colon | Kip Wells | | 287 | 250 | 37 |
| 2000-05-29 | @ SEA | 50 | L 4-5 | 28-22 | 1 | 34,429 | Mike Sirotka | John Halama | John Halama | Mike Sirotka | Kazuhiro Sasaki | 291 | 255 | 36 |
| 2000-05-30 | @ SEA | 51 | W 2-1 | 29-22 | 1 | 25,788 | James Baldwin | Paul Abbott | James Baldwin | Paul Abbott | Keith Foulke | 293 | 256 | 37 |
| 2000-05-31 | @ SEA | 52 | W 4-3 | 30-22 | 1 | 35,823 | Cal Eldred | Aaron Sele | Bob Howry | Kazuhiro Sasaki | Keith Foulke | 297 | 259 | 38 |
| 2000-06-02 | @ HOU | 53 | W 7-4 | 31-22 | 1 | 39,028 | Jim Parque | Shane Reynolds | Jim Parque | Shane Reynolds | Keith Foulke | 304 | 263 | 41 |
| 2000-06-03 | @ HOU | 54 | L 1-6 | 31-23 | 1 | 39,459 | Kip Wells | Chris Holt | Chris Holt | Kip Wells | | 305 | 269 | 36 |
| 2000-06-04 | @ HOU | 55 | W 7-3 | 32-23 | 1 | 41,117 | Mike Sirotka | Octavio Dotel | Mike Sirotka | Octavio Dotel | | 312 | 272 | 40 |
| 2000-06-05 | @ CIN | 56 | W 4-3 | 33-23 | 1 | 26,624 | James Baldwin | Steve Parris | James Baldwin | Steve Parris | Keith Foulke | 316 | 275 | 41 |
| 2000-06-06 | @ CIN | 57 | W 17-12 | 34-23 | 1 | 28,908 | Cal Eldred | Ron Villone | Cal Eldred | Ron Villone | | 333 | 287 | 46 |
| 2000-06-07 | @ CIN | 58 | W 6-4 | 35-23 | 1 | 31,023 | Jim Parque | Rob Bell | Jim Parque | Rob Bell | Keith Foulke | 339 | 291 | 48 |
| 2000-06-09 | vs CHN | 59 | W 6-5 | 36-23 | 1 | 44,140 | Kip Wells | Jon Lieber | Jesus Pena | Todd Van Poppel | | 345 | 296 | 49 |
| 2000-06-10 | vs CHN | 60 | W 4-3 | 37-23 | 1 | 43,806 | Mike Sirotka | Kerry Wood | Mike Sirotka | Kerry Wood | Keith Foulke | 349 | 299 | 50 |
| 2000-06-11 | vs CHN | 61 | L 5-6 | 37-24 | 1 | 43,158 | James Baldwin | Ismael Valdez | Todd Van Poppel | Jesus Pena | Rick Aguilera | 354 | 305 | 49 |
| 2000-06-12 | @ CLE | 62 | W 8-7 | 38-24 | 1 | 43,229 | Cal Eldred | Paul Rigdon | Cal Eldred | Paul Rigdon | Keith Foulke | 362 | 312 | 50 |
| 2000-06-13 | @ CLE | 63 | W 4-3 | 39-24 | 1 | 43,233 | Jim Parque | Bartolo Colon | Bill Simas | Justin Speier | Bob Howry | 366 | 315 | 51 |
| 2000-06-14 | @ CLE | 64 | W 11-4 | 40-24 | 1 | 43,284 | Kip Wells | Jim Brower | Kevin Beirne | Jim Brower | | 377 | 319 | 58 |
| 2000-06-15 | @ NYA | 65 | W 12-3 | 41-24 | 1 | 30,803 | Mike Sirotka | Andy Pettitte | Mike Sirotka | Andy Pettitte | | 389 | 322 | 67 |
| 2000-06-16 | @ NYA | 66 | W 3-1 | 42-24 | 1 | 41,910 | James Baldwin | David Cone | James Baldwin | Mike Stanton | Bob Howry | 392 | 323 | 69 |
| 2000-06-17 | @ NYA | 67 | W 10-9 | 43-24 | 1 | 54,053 | Cal Eldred | Jake Westbrook | Cal Eldred | Jake Westbrook | Keith Foulke | 402 | 332 | 70 |
| 2000-06-18 | @ NYA | 68 | W 17-4 | 44-24 | 1 | 52,856 | Jim Parque | Orlando Hernandez | Jim Parque | Orlando Hernandez | | 419 | 336 | 83 |
| 2000-06-19 | vs CLE | 69 | W 6-1 | 45-24 | 1 | 43,062 | Kip Wells | Bartolo Colon | Kip Wells | Bartolo Colon | | 425 | 337 | 88 |
| 2000-06-20 | vs CLE | 70 | L 1-4 | 45-25 | 1 | 20,005 | Mike Sirotka | Jim Brower | Jim Brower | Mike Sirotka | Steve Karsay | 426 | 341 | 85 |
| 2000-06-21 | vs CLE | 71 | L 6-8 | 45-26 | 1 | 23,516 | James Baldwin | Dave Burba | Dave Burba | James Baldwin | Steve Karsay | 432 | 349 | 83 |
| 2000-06-22 | vs CLE | 72 | W 6-0 | 46-26 | 1 | 23,374 | Cal Eldred | Chuck Finley | Cal Eldred | Chuck Finley | | 438 | 349 | 89 |
| 2000-06-23 | vs NYA | 73 | W 4-3 | 47-26 | 1 | 38,773 | Jim Parque | Ben Ford | Sean Lowe | Mariano Rivera | | 442 | 352 | 90 |
| 2000-06-24 | vs NYA | 74 | L 8-12 | 47-27 | 1 | 32,623 | Kip Wells | Ramiro Mendoza | Ramiro Mendoza | Kip Wells | Mariano Rivera | 450 | 364 | 86 |
| 2000-06-25 | vs NYA | 75 | W 8-7 | 48-27 | 1 | 40,817 | Mike Sirotka | Andy Pettitte | Mike Sirotka | Andy Pettitte | Bob Howry | 458 | 371 | 87 |
| 2000-06-27 | vs MIN | 76 | L 4-7 | 48-28 | 1 | 20,283 | James Baldwin | Joe Mays | Joe Mays | James Baldwin | Bob Wells | 462 | 378 | 84 |
| 2000-06-28 | vs MIN | 77 | W 7-3 | 49-28 | 1 | 17,541 | Cal Eldred | Mike Lincoln | Cal Eldred | Mike Lincoln | | 469 | 381 | 88 |
| 2000-06-29 | vs MIN | 78 | L 1-10 | 49-29 | 1 | 21,239 | Kip Wells | Eric Milton | Eric Milton | Kip Wells | | 470 | 391 | 79 |
| 2000-06-30 | vs BOS | 79 | W 10-4 | 50-29 | 1 | 32,157 | Jim Parque | Hipolito Pichardo | Jim Parque | Hipolito Pichardo | | 480 | 395 | 85 |
| 2000-07-01 | vs BOS | 80 | W 7-2 | 51-29 | 1 | 28,006 | Mike Sirotka | Paxton Crawford | Mike Sirotka | Paxton Crawford | | 487 | 397 | 90 |
| 2000-07-02 | vs BOS | 81 | W 8-2 | 52-29 | 1 | 32,934 | James Baldwin | Pete Schourek | James Baldwin | Pete Schourek | | 495 | 399 | 96 |
| 2000-07-03 | @ KCA | 82 | W 14-10 | 53-29 | 1 | 24,496 | Cal Eldred | Jay Witasick | Jesus Pena | Jose Santiago | | 509 | 409 | 100 |
| 2000-07-04 | @ KCA | 83 | L 7-10 | 53-30 | 1 | 29,884 | Jon Garland | Chad Durbin | Jerry Spradlin | Jon Garland | | 516 | 419 | 97 |
| 2000-07-05 | @ KCA | 84 | W 6-3 | 54-30 | 1 | 15,009 | Jim Parque | Dan Reichert | Kelly Wunsch | Doug Bochtler | | 522 | 422 | 100 |
| 2000-07-07 | @ CHN | 85 | W 4-2 | 55-30 | 1 | 39,112 | Mike Sirotka | Kerry Wood | Sean Lowe | Todd Van Poppel | Jesus Pena | 526 | 424 | 102 |
| 2000-07-08 | @ CHN | 86 | L 2-9 | 55-31 | 1 | 38,933 | James Baldwin | Jon Lieber | Jon Lieber | James Baldwin | | 528 | 433 | 95 |
| 2000-07-09 | @ CHN | 87 | L 6-9 | 55-32 | 1 | 38,706 | Cal Eldred | Kevin Tapani | Kevin Tapani | Bill Simas | Tim Worrell | 534 | 442 | 92 |
| 2000-07-13 | vs SLN | 88 | L 5-13 | 55-33 | 1 | 32,263 | Mike Sirotka | Andy Benes | Andy Benes | Mike Sirotka | | 539 | 455 | 84 |
| 2000-07-14 | vs SLN | 89 | L 4-9 | 55-34 | 1 | 34,862 | Cal Eldred | Garrett Stephenson | Garrett Stephenson | Kelly Wunsch | | 543 | 464 | 79 |
| 2000-07-15 | vs SLN | 90 | W 15-7 | 56-34 | 1 | 40,681 | Jim Parque | Darryl Kile | Jim Parque | Darryl Kile | | 558 | 471 | 87 |
| 2000-07-16 | vs MIL | 91 | W 11-5 | 57-34 | 1 | 30,050 | James Baldwin | John Snyder | James Baldwin | John Snyder | | 569 | 476 | 93 |
| 2000-07-17 | vs MIL | 92 | W 11-2 | 58-34 | 1 | 31,369 | Jon Garland | Jason Bere | Jon Garland | Jason Bere | | 580 | 478 | 102 |
| 2000-07-18 | vs MIL | 93 | W 7-5 | 59-34 | 1 | 18,542 | Mike Sirotka | Jamey Wright | Mike Sirotka | Jamey Wright | Kelly Wunsch | 587 | 483 | 104 |
| 2000-07-19 | @ MIN | 94 | W 3-2 | 60-34 | 1 | 12,494 | Mark Buehrle | Eric Milton | Mark Buehrle | Eric Milton | Keith Foulke | 590 | 485 | 105 |
| 2000-07-20 | @ MIN | 95 | L 1-5 | 60-35 | 1 | 18,676 | Jim Parque | Joe Mays | Joe Mays | Jim Parque | | 591 | 490 | 101 |
| 2000-07-21 | @ BOS | 96 | W 8-5 | 61-35 | 1 | 33,869 | James Baldwin | Tim Wakefield | Bill Simas | Hipolito Pichardo | Bob Howry | 599 | 495 | 104 |
| 2000-07-22 | @ BOS | 97 | L 6-8 | 61-36 | 1 | 33,384 | Jon Garland | Jeff Fassero | Jeff Fassero | Jon Garland | | 605 | 503 | 102 |
| 2000-07-23 | @ BOS | 98 | L 0-1 | 61-37 | 1 | 33,224 | Mike Sirotka | Pedro Martinez | Pedro Martinez | Mike Sirotka | | 605 | 504 | 101 |
| 2000-07-24 | vs KCA | 99 | W 7-6 | 62-37 | 1 | 34,473 | Mark Buehrle | Mac Suzuki | Kelly Wunsch | Mac Suzuki | Keith Foulke | 612 | 510 | 102 |
| 2000-07-25 | vs KCA | 100 | L 1-6 | 62-38 | 1 | 21,091 | Jim Parque | Jeff Suppan | Jeff Suppan | Jim Parque | | 613 | 516 | 97 |
| 2000-07-26 | vs KCA | 101 | L 6-7 | 62-39 | 1 | 26,615 | James Baldwin | Dan Reichert | Jerry Spradlin | Bob Howry | Ricky Bottalico | 619 | 523 | 96 |
| 2000-07-27 | @ ANA | 102 | W 6-5 | 63-39 | 1 | 24,394 | Jon Garland | Brian Cooper | Jon Garland | Brian Cooper | Keith Foulke | 625 | 528 | 97 |
| 2000-07-28 | @ ANA | 103 | L 7-10 | 63-40 | 1 | 40,711 | Mike Sirotka | Ken Hill | Mike Holtz | Kevin Beirne | Troy Percival | 632 | 538 | 94 |
| 2000-07-29 | @ ANA | 104 | L 5-6 | 63-41 | 1 | 25,881 | Mark Buehrle | Kent Bottenfield | Kent Bottenfield | Lorenzo Barcelo | Troy Percival | 637 | 544 | 93 |
| 2000-07-30 | @ ANA | 105 | W 11-7 | 64-41 | 1 | 27,538 | Jim Parque | Seth Etherton | Keith Foulke | Al Levine | | 648 | 551 | 97 |
| 2000-08-01 | @ TEX | 106 | W 4-3 | 65-41 | 1 | 37,784 | James Baldwin | Ryan Glynn | Bob Howry | John Wetteland | | 652 | 554 | 98 |
| 2000-08-02 | @ TEX | 107 | L 2-7 | 65-42 | 1 | 36,786 | Jon Garland | Rick Helling | Rick Helling | Jon Garland | Tim Crabtree | 654 | 561 | 93 |
| 2000-08-04 | vs OAK | 108 | L 3-5 | 65-43 | 1 | 30,019 | Mike Sirotka | Kevin Appier | Kevin Appier | Mike Sirotka | Jason Isringhausen | 657 | 566 | 91 |
| 2000-08-05 | vs OAK | 109 | W 4-3 | 66-43 | 1 | 35,314 | Jim Parque | Gil Heredia | Keith Foulke | T.J. Mathews | | 661 | 569 | 92 |
| 2000-08-06 | vs OAK | 110 | W 13-0 | 67-43 | 1 | 32,952 | James Baldwin | Tim Hudson | James Baldwin | Tim Hudson | | 674 | 569 | 105 |
| 2000-08-08 | vs SEA | 111 | L 4-12 | 67-45 | 1 | 23,647 | Jon Garland | Joel Pineiro | Joel Pineiro | Jon Garland | Brett Tomko | 678 | 581 | 97 |
| 2000-08-08 | vs SEA | 112 | L 5-7 | 67-45 | 1 | 23,647 | Lorenzo Barcelo | Freddy Garcia | Freddy Garcia | Mark Buehrle | Kazuhiro Sasaki | 683 | 588 | 95 |
| 2000-08-09 | vs SEA | 113 | W 19-3 | 68-45 | 1 | 24,947 | Mike Sirotka | Jamie Moyer | Mike Sirotka | Jamie Moyer | | 702 | 591 | 111 |
| 2000-08-10 | vs SEA | 114 | L 3-6 | 68-46 | 1 | 23,924 | Rocky Biddle | Aaron Sele | Aaron Sele | Rocky Biddle | Kazuhiro Sasaki | 705 | 597 | 108 |
| 2000-08-11 | @ TBA | 115 | W 6-5 | 69-46 | 1 | 18,370 | Jim Parque | Ryan Rupe | Mark Buehrle | Paul Wilson | Keith Foulke | 711 | 602 | 109 |
| 2000-08-12 | @ TBA | 116 | W 5-4 | 70-46 | 1 | 27,538 | James Baldwin | Bryan Rekar | Mark Buehrle | Roberto Hernandez | Keith Foulke | 716 | 606 | 110 |
| 2000-08-13 | @ TBA | 117 | L 3-5 | 70-47 | 1 | 19,685 | Jon Garland | Albie Lopez | Albie Lopez | Bob Howry | | 719 | 611 | 108 |
| 2000-08-14 | @ BAL | 118 | L 2-8 | 70-48 | 1 | 40,047 | Mike Sirotka | Jose Mercedes | Jose Mercedes | Mike Sirotka | | 721 | 619 | 102 |
| 2000-08-15 | @ BAL | 119 | W 14-4 | 71-48 | 1 | 37,707 | Rocky Biddle | Jason Johnson | Rocky Biddle | Jason Johnson | | 735 | 623 | 112 |
| 2000-08-16 | @ BAL | 120 | W 7-3 | 72-48 | 1 | 39,079 | Jim Parque | Mike Mussina | Jim Parque | Mike Mussina | | 742 | 626 | 116 |
| 2000-08-17 | @ BAL | 121 | L 3-5 | 72-49 | 1 | 40,205 | James Baldwin | John Parrish | John Parrish | James Baldwin | | 745 | 631 | 114 |
| 2000-08-18 | vs TBA | 122 | W 5-2 | 73-49 | 1 | 25,160 | Jon Garland | Bryan Rekar | Jon Garland | Bryan Rekar | Keith Foulke | 750 | 633 | 117 |
| 2000-08-19 | vs TBA | 123 | W 7-0 | 74-49 | 1 | 38,926 | Mike Sirotka | Albie Lopez | Mike Sirotka | Albie Lopez | | 757 | 633 | 124 |
| 2000-08-20 | vs TBA | 124 | L 11-12 | 74-50 | 1 | 27,744 | Rocky Biddle | Dave Eiland | Esteban Yan | Keith Foulke | Roberto Hernandez | 768 | 645 | 123 |
| 2000-08-21 | vs TBA | 125 | L 4-11 | 74-51 | 1 | 31,744 | Jim Parque | Tanyon Sturtze | Tanyon Sturtze | Jim Parque | | 772 | 656 | 116 |
| 2000-08-23 | vs BAL | 126 | W 8-4 | 75-51 | 1 | 22,528 | Sean Lowe | John Parrish | Lorenzo Barcelo | John Parrish | | 780 | 660 | 120 |
| 2000-08-24 | vs BAL | 127 | L 5-8 | 75-52 | 1 | 20,007 | Ken Hill | Jose Mercedes | Jose Mercedes | Ken Hill | | 785 | 668 | 117 |
| 2000-08-25 | @ SEA | 128 | W 4-1 | 76-52 | 1 | 44,745 | Mike Sirotka | Aaron Sele | Mike Sirotka | Aaron Sele | Keith Foulke | 789 | 669 | 120 |
| 2000-08-26 | @ SEA | 129 | L 5-11 | 76-53 | 1 | 45,191 | Rocky Biddle | John Halama | John Halama | Rocky Biddle | | 794 | 680 | 114 |
| 2000-08-27 | @ SEA | 130 | W 2-1 | 77-53 | 1 | 45,525 | Sean Lowe | Freddy Garcia | Lorenzo Barcelo | Freddy Garcia | Keith Foulke | 796 | 681 | 115 |
| 2000-08-28 | @ OAK | 131 | L 0-3 | 77-54 | 1 | 12,436 | Jim Parque | Tim Hudson | Tim Hudson | Jim Parque | | 796 | 684 | 112 |
| 2000-08-29 | @ OAK | 132 | W 3-0 | 78-54 | 1 | 12,129 | James Baldwin | Barry Zito | James Baldwin | Barry Zito | Keith Foulke | 799 | 684 | 115 |
| 2000-08-30 | @ OAK | 133 | W 8-3 | 79-54 | 1 | 19,458 | Mike Sirotka | Kevin Appier | Mike Sirotka | Kevin Appier | Bob Howry | 807 | 687 | 120 |
| 2000-09-01 | vs ANA | 134 | W 9-8 | 80-54 | 1 | 16,377 | Sean Lowe | Scott Schoeneweis | Matt Ginter | Shigetoshi Hasegawa | Keith Foulke | 816 | 695 | 121 |
| 2000-09-02 | vs ANA | 135 | W 13-6 | 81-54 | 1 | 29,785 | Jim Parque | Kent Mercker | Jim Parque | Kent Mercker | | 829 | 701 | 128 |
| 2000-09-03 | vs ANA | 136 | W 13-12 | 82-54 | 1 | 22,020 | James Baldwin | Ramon Ortiz | Kelly Wunsch | Shigetoshi Hasegawa | Keith Foulke | 842 | 713 | 129 |
| 2000-09-04 | vs TEX | 137 | L 4-5 | 82-55 | 1 | 29,614 | Jon Garland | Doug Davis | Doug Davis | Jon Garland | John Wetteland | 846 | 718 | 128 |
| 2000-09-05 | vs TEX | 138 | L 1-2 | 82-56 | 1 | 13,899 | Mike Sirotka | Darren Oliver | Jonathan Johnson | Bob Howry | John Wetteland | 847 | 720 | 127 |
| 2000-09-06 | vs TEX | 139 | W 13-1 | 83-56 | 1 | 15,622 | Kip Wells | Rick Helling | Kip Wells | Rick Helling | | 860 | 721 | 139 |
| 2000-09-07 | vs TEX | 140 | W 10-6 | 84-56 | 1 | 18,219 | Jim Parque | Kenny Rogers | Lorenzo Barcelo | Jeff Zimmerman | Keith Foulke | 870 | 727 | 143 |
| 2000-09-08 | @ CLE | 141 | W 5-4 | 85-56 | 1 | 42,526 | James Baldwin | Steve Woodard | Mark Buehrle | Steve Woodard | Keith Foulke | 875 | 731 | 144 |
| 2000-09-09 | @ CLE | 142 | L 3-9 | 85-57 | 1 | 42,561 | Jon Garland | Dave Burba | Dave Burba | Jon Garland | | 878 | 740 | 138 |
| 2000-09-11 | vs DET | 143 | W 10-3 | 86-57 | 1 | 21,527 | Mike Sirotka | Brian Moehler | Mike Sirotka | Brian Moehler | Bob Howry | 888 | 743 | 145 |
| 2000-09-12 | vs DET | 144 | L 3-10 | 86-58 | 1 | 15,297 | Kip Wells | Dave Mlicki | Dave Mlicki | Kip Wells | | 891 | 753 | 138 |
| 2000-09-13 | vs DET | 145 | W 1-0 | 87-58 | 1 | 16,651 | Jim Parque | Jeff Weaver | Jim Parque | Jeff Weaver | Keith Foulke | 892 | 753 | 139 |
| 2000-09-15 | vs TOR | 146 | L 5-6 | 87-59 | 1 | 23,105 | Jon Garland | Steve Trachsel | Kelvim Escobar | Jon Garland | Billy Koch | 897 | 759 | 138 |
| 2000-09-16 | vs TOR | 147 | W 6-3 | 88-59 | 1 | 33,204 | Mike Sirotka | Chris Carpenter | Kelly Wunsch | Kelvim Escobar | Keith Foulke | 903 | 762 | 141 |
| 2000-09-17 | vs TOR | 148 | L 1-14 | 88-60 | 1 | 26,113 | Kip Wells | Joey Hamilton | Lance Painter | Kip Wells | | 904 | 776 | 128 |
| 2000-09-18 | @ DET | 149 | L 2-5 | 88-61 | 1 | 22,718 | Jim Parque | Jeff Weaver | Jeff Weaver | Lorenzo Barcelo | Todd Jones | 906 | 781 | 125 |
| 2000-09-19 | @ DET | 150 | W 6-2 | 89-61 | 1 | 24,951 | Sean Lowe | Steve Sparks | Sean Lowe | Steve Sparks | | 912 | 783 | 129 |
| 2000-09-20 | @ DET | 151 | W 13-6 | 90-61 | 1 | 28,422 | Jon Garland | Brian Moehler | Jon Garland | Brian Moehler | | 925 | 789 | 136 |
| 2000-09-21 | @ MIN | 152 | W 9-4 | 91-61 | 1 | 6,688 | Mike Sirotka | Johan Santana | Mike Sirotka | Johan Santana | | 934 | 793 | 141 |
| 2000-09-22 | @ MIN | 153 | W 5-4 | 92-61 | 1 | 9,060 | Kip Wells | Brad Radke | Lorenzo Barcelo | Bob Wells | Keith Foulke | 939 | 797 | 142 |
| 2000-09-23 | @ MIN | 154 | W 5-3 | 93-61 | 1 | 20,263 | Jim Parque | Eric Milton | Jim Parque | Eric Milton | Keith Foulke | 944 | 800 | 144 |
| 2000-09-24 | @ MIN | 155 | L 5-6 | 93-62 | 1 | 9,716 | Sean Lowe | Joe Mays | Eddie Guardado | Kevin Beirne | | 949 | 806 | 143 |
| 2000-09-25 | @ CLE | 156 | L 2-9 | 93-63 | 1 | 42,500 | Jon Garland | Dave Burba | Dave Burba | Jon Garland | | 951 | 815 | 136 |
| 2000-09-26 | vs BOS | 157 | L 3-4 | 93-64 | 1 | 23,319 | Kevin Beirne | Pedro Martinez | Pedro Martinez | Kevin Beirne | Derek Lowe | 954 | 819 | 135 |
| 2000-09-27 | vs BOS | 158 | L 1-2 | 93-65 | 1 | 16,368 | Cal Eldred | Paxton Crawford | Paxton Crawford | James Baldwin | Derek Lowe | 955 | 821 | 134 |
| 2000-09-28 | vs BOS | 159 | L 6-7 | 93-66 | 1 | 18,326 | Mike Sirotka | Ramon Martinez | Rod Beck | Bill Simas | Derek Lowe | 961 | 828 | 133 |
| 2000-09-29 | vs KCA | 160 | W 6-4 | 94-66 | 1 | 17,735 | Jim Parque | Dan Reichert | Chad Bradford | Dan Reichert | Keith Foulke | 967 | 832 | 135 |
| 2000-09-30 | vs KCA | 161 | W 9-1 | 95-66 | 1 | 29,692 | Kip Wells | Blake Stein | Kip Wells | Blake Stein | | 976 | 833 | 143 |
| 2000-10-01 | vs KCA | 162 | L 2-6 | 95-67 | 1 | 30,071 | James Baldwin | Chris Fussell | Chris Fussell | James Baldwin | | 978 | 839 | 139 |