| 1980-04-10 | @ SDN | 1 | L 4-6 | 0-1 | 6 | 29,535 | Bob Knepper | Randy Jones | Randy Jones | Bob Knepper | Bob Shirley | 4 | 6 | -2 |
| 1980-04-11 | @ SDN | 2 | L 3-5 | 0-2 | 6 | 20,569 | Ed Whitson | Rick Wise | Rollie Fingers | Gary Lavelle | | 7 | 11 | -4 |
| 1980-04-12 | @ SDN | 3 | L 2-4 | 0-3 | 6 | 22,410 | John Montefusco | John Curtis | John Curtis | John Montefusco | Bob Shirley | 9 | 15 | -6 |
| 1980-04-13 | @ SDN | 4 | W 3-1 | 1-3 | 5 | 16,314 | Vida Blue | Eric Rasmussen | Vida Blue | Eric Rasmussen | Gary Lavelle | 12 | 16 | -4 |
| 1980-04-14 | @ CIN | 5 | L 5-6 | 1-4 | 5 | 10,296 | Bob Knepper | Paul Moskau | Dave Tomlin | Gary Lavelle | | 17 | 22 | -5 |
| 1980-04-15 | @ CIN | 6 | L 3-8 | 1-5 | 5 | 11,544 | Ed Whitson | Tom Seaver | Tom Seaver | Ed Whitson | Tom Hume | 20 | 30 | -10 |
| 1980-04-16 | @ CIN | 7 | L 3-5 | 1-6 | 5 | 15,603 | John Montefusco | Mike LaCoss | Mike LaCoss | John Montefusco | | 23 | 35 | -12 |
| 1980-04-17 | vs SDN | 8 | W 7-3 | 2-6 | 5 | 51,123 | Vida Blue | Eric Rasmussen | Vida Blue | Eric Rasmussen | | 30 | 38 | -8 |
| 1980-04-18 | vs SDN | 9 | W 5-2 | 3-6 | 5 | 12,241 | Bob Knepper | Randy Jones | Bob Knepper | Randy Jones | | 35 | 40 | -5 |
| 1980-04-19 | vs SDN | 10 | L 0-3 | 3-7 | 5 | 11,024 | Ed Whitson | Gary Lucas | Gary Lucas | Ed Whitson | Rollie Fingers | 35 | 43 | -8 |
| 1980-04-20 | vs SDN | 11 | W 5-1 | 4-7 | 5 | 26,048 | John Montefusco | Rick Wise | John Montefusco | Rick Wise | | 40 | 44 | -4 |
| 1980-04-21 | @ LAN | 12 | L 3-4 | 4-8 | 5 | 29,779 | Vida Blue | Burt Hooton | Burt Hooton | Vida Blue | Steve Howe | 43 | 48 | -5 |
| 1980-04-22 | @ LAN | 13 | L 0-6 | 4-9 | 5 | 21,691 | Bob Knepper | Don Sutton | Don Sutton | Bob Knepper | | 43 | 54 | -11 |
| 1980-04-23 | @ LAN | 14 | L 0-4 | 4-10 | 5 | 24,822 | Ed Whitson | Dave Goltz | Dave Goltz | Ed Whitson | | 43 | 58 | -15 |
| 1980-04-24 | @ LAN | 15 | L 2-5 | 4-11 | 6 | 30,687 | John Montefusco | Bob Welch | Jerry Reuss | Gary Lavelle | | 45 | 63 | -18 |
| 1980-04-25 | vs CIN | 16 | W 4-3 | 5-11 | 6 | 15,345 | Vida Blue | Tom Seaver | Greg Minton | Doug Bair | | 49 | 66 | -17 |
| 1980-04-26 | vs CIN | 17 | W 3-1 | 6-11 | 5 | 13,360 | Bob Knepper | Mike LaCoss | Bob Knepper | Mike LaCoss | | 52 | 67 | -15 |
| 1980-04-27 | vs CIN | 18 | L 1-3 | 6-12 | 6 | 32,084 | Ed Whitson | Frank Pastore | Frank Pastore | Ed Whitson | | 53 | 70 | -17 |
| 1980-04-29 | vs LAN | 19 | L 0-5 | 6-13 | 6 | 16,940 | John Montefusco | Dave Goltz | Dave Goltz | John Montefusco | | 53 | 75 | -22 |
| 1980-04-30 | vs LAN | 20 | L 3-4 | 6-14 | 6 | 19,006 | Vida Blue | Bob Welch | Bob Welch | Greg Minton | Steve Howe | 56 | 79 | -23 |
| 1980-05-02 | @ MON | 21 | L 3-4 | 6-15 | 6 | 8,953 | Bob Knepper | Ross Grimsley | Stan Bahnsen | Gary Lavelle | | 59 | 83 | -24 |
| 1980-05-03 | @ MON | 22 | W 3-2 | 7-15 | 6 | 18,622 | Ed Whitson | Scott Sanderson | Randy Moffitt | Elias Sosa | Al Holland | 62 | 85 | -23 |
| 1980-05-04 | @ MON | 23 | W 8-4 | 8-16 | 6 | 0 | John Montefusco | Steve Rogers | John Montefusco | Steve Rogers | Greg Minton | 70 | 89 | -19 |
| 1980-05-04 | @ MON | 24 | L 4-6 | 8-16 | 6 | 33,483 | Ed Halicki | Bill Lee | Stan Bahnsen | Randy Moffitt | Elias Sosa | 74 | 95 | -21 |
| 1980-05-05 | @ SLN | 25 | L 5-9 | 8-17 | 6 | 10,366 | Vida Blue | Pete Vuckovich | Pete Vuckovich | Vida Blue | Jim Kaat | 79 | 104 | -25 |
| 1980-05-06 | @ SLN | 26 | L 7-10 | 8-18 | 6 | 11,490 | Bob Knepper | Don Hood | Donnie Moore | Bob Knepper | Pedro Borbon | 86 | 114 | -28 |
| 1980-05-07 | @ SLN | 27 | L 2-12 | 8-19 | 6 | 12,464 | Ed Whitson | Bob Forsch | Bob Forsch | Ed Whitson | | 88 | 126 | -38 |
| 1980-05-09 | @ CHN | 28 | W 6-3 | 9-19 | 6 | 8,403 | Vida Blue | Dennis Lamp | Vida Blue | Dennis Lamp | | 94 | 129 | -35 |
| 1980-05-10 | @ CHN | 29 | L 9-15 | 9-20 | 6 | 26,646 | Bob Knepper | Lynn McGlothen | Lynn McGlothen | Bob Knepper | | 103 | 144 | -41 |
| 1980-05-11 | @ CHN | 30 | W 3-0 | 10-20 | 6 | 15,435 | Ed Whitson | Mike Krukow | Ed Whitson | Mike Krukow | | 106 | 144 | -38 |
| 1980-05-13 | vs PIT | 31 | W 5-0 | 11-20 | 6 | 13,798 | Vida Blue | Bert Blyleven | Vida Blue | Bert Blyleven | | 111 | 144 | -33 |
| 1980-05-14 | vs PIT | 32 | L 2-3 | 11-21 | 6 | 8,734 | Bob Knepper | Jim Bibby | Jim Bibby | Bob Knepper | Kent Tekulve | 113 | 147 | -34 |
| 1980-05-15 | vs PIT | 33 | L 2-3 | 11-22 | 6 | 7,781 | Ed Whitson | Don Robinson | Enrique Romo | Tom Griffin | | 115 | 150 | -35 |
| 1980-05-16 | vs SLN | 34 | W 4-3 | 12-22 | 6 | 16,860 | Ed Halicki | Bob Forsch | Al Holland | Bob Forsch | | 119 | 153 | -34 |
| 1980-05-17 | vs SLN | 35 | W 4-2 | 13-22 | 6 | 12,134 | Vida Blue | John Fulgham | Vida Blue | Bob Sykes | Gary Lavelle | 123 | 155 | -32 |
| 1980-05-18 | vs SLN | 36 | W 6-5 | 14-22 | 5 | 21,351 | Bob Knepper | Don Hood | Bob Knepper | Don Hood | Al Holland | 129 | 160 | -31 |
| 1980-05-20 | vs CHN | 37 | W 2-0 | 15-22 | 5 | 8,652 | Ed Whitson | Mike Krukow | Ed Whitson | Mike Krukow | | 131 | 160 | -29 |
| 1980-05-21 | vs CHN | 38 | W 4-1 | 16-22 | 5 | 8,929 | Vida Blue | Rick Reuschel | Vida Blue | Rick Reuschel | | 135 | 161 | -26 |
| 1980-05-23 | @ PIT | 39 | L 4-5 | 16-23 | 5 | 9,619 | Bob Knepper | Jim Bibby | Grant Jackson | Al Holland | | 139 | 166 | -27 |
| 1980-05-24 | @ PIT | 40 | W 10-9 | 17-23 | 5 | 11,591 | Ed Whitson | Eddie Solomon | Tom Griffin | Rod Scurry | | 149 | 175 | -26 |
| 1980-05-25 | @ PIT | 41 | W 5-2 | 18-23 | 5 | 42,626 | Vida Blue | John Candelaria | Vida Blue | John Candelaria | | 154 | 177 | -23 |
| 1980-05-26 | @ ATL | 42 | L 1-2 | 18-24 | 5 | 5,822 | Allen Ripley | Tommy Boggs | Tommy Boggs | Greg Minton | Larry Bradford | 155 | 179 | -24 |
| 1980-05-27 | @ ATL | 43 | L 3-6 | 18-25 | 5 | 5,277 | Bob Knepper | Larry McWilliams | Larry McWilliams | Bob Knepper | Gene Garber | 158 | 185 | -27 |
| 1980-05-28 | @ ATL | 44 | L 2-3 | 18-26 | 5 | 5,500 | Ed Whitson | Doyle Alexander | Al Hrabosky | Gary Lavelle | | 160 | 188 | -28 |
| 1980-05-30 | vs HOU | 45 | W 3-2 | 19-26 | 5 | 10,511 | Vida Blue | Ken Forsch | Vida Blue | Ken Forsch | | 163 | 190 | -27 |
| 1980-05-31 | vs HOU | 46 | L 0-5 | 19-27 | 5 | 11,649 | John Montefusco | J.R. Richard | J.R. Richard | John Montefusco | | 163 | 195 | -32 |
| 1980-06-01 | vs HOU | 47 | W 6-2 | 20-27 | 5 | 19,801 | Bob Knepper | Joe Niekro | Bob Knepper | Joe Niekro | | 169 | 197 | -28 |
| 1980-06-02 | vs ATL | 48 | L 2-4 | 20-28 | 6 | 3,768 | Ed Whitson | Phil Niekro | Phil Niekro | Ed Whitson | | 171 | 201 | -30 |
| 1980-06-03 | vs ATL | 49 | W 3-2 | 21-28 | 5 | 9,294 | Vida Blue | Larry McWilliams | Greg Minton | Larry Bradford | | 174 | 203 | -29 |
| 1980-06-04 | vs ATL | 50 | L 2-7 | 21-29 | 6 | 5,593 | John Montefusco | Rick Matula | Rick Matula | John Montefusco | | 176 | 210 | -34 |
| 1980-06-06 | @ HOU | 51 | L 0-2 | 21-30 | 6 | 26,822 | Bob Knepper | J.R. Richard | J.R. Richard | Bob Knepper | | 176 | 212 | -36 |
| 1980-06-07 | @ HOU | 52 | L 0-3 | 21-31 | 6 | 42,263 | Ed Whitson | Joe Niekro | Joe Niekro | Ed Whitson | | 176 | 215 | -39 |
| 1980-06-08 | @ HOU | 53 | L 4-5 | 21-32 | 6 | 28,327 | Vida Blue | Nolan Ryan | Joe Sambito | Greg Minton | | 180 | 220 | -40 |
| 1980-06-09 | @ PHI | 54 | W 3-1 | 22-32 | 6 | 28,702 | John Montefusco | Steve Carlton | Allen Ripley | Dickie Noles | Greg Minton | 183 | 221 | -38 |
| 1980-06-10 | @ PHI | 55 | L 3-4 | 22-33 | 6 | 32,635 | Bob Knepper | Bob Walk | Kevin Saucier | Bob Knepper | Ron Reed | 186 | 225 | -39 |
| 1980-06-11 | @ PHI | 56 | W 7-4 | 23-33 | 6 | 37,844 | Ed Whitson | Randy Lerch | Ed Whitson | Randy Lerch | Greg Minton | 193 | 229 | -36 |
| 1980-06-13 | @ NYN | 57 | W 3-1 | 24-33 | 6 | 24,679 | Vida Blue | Ray Burris | Vida Blue | Ray Burris | | 196 | 230 | -34 |
| 1980-06-14 | @ NYN | 58 | L 6-7 | 24-34 | 6 | 22,918 | John Montefusco | Pete Falcone | Jeff Reardon | Allen Ripley | | 202 | 237 | -35 |
| 1980-06-15 | @ NYN | 59 | W 3-0 | 25-34 | 4 | 44,910 | Bob Knepper | Pat Zachry | Bob Knepper | Pat Zachry | | 205 | 237 | -32 |
| 1980-06-16 | vs MON | 60 | W 5-1 | 26-34 | 4 | 4,756 | Ed Whitson | Charlie Lea | Ed Whitson | Charlie Lea | | 210 | 238 | -28 |
| 1980-06-17 | vs MON | 61 | L 1-2 | 26-35 | 5 | 19,362 | Vida Blue | David Palmer | David Palmer | Vida Blue | Woodie Fryman | 211 | 240 | -29 |
| 1980-06-18 | vs NYN | 62 | W 8-5 | 27-35 | 4 | 5,035 | John Montefusco | Ray Burris | John Montefusco | Ray Burris | Greg Minton | 219 | 245 | -26 |
| 1980-06-19 | vs NYN | 63 | W 4-3 | 28-35 | 4 | 5,179 | Bob Knepper | Mark Bomback | Gary Lavelle | Neil Allen | | 223 | 248 | -25 |
| 1980-06-20 | vs PHI | 64 | W 5-1 | 29-35 | 4 | 9,490 | Allen Ripley | Dan Larson | Allen Ripley | Dan Larson | | 228 | 249 | -21 |
| 1980-06-21 | vs PHI | 65 | W 9-3 | 30-35 | 4 | 11,809 | Ed Whitson | Randy Lerch | Ed Whitson | Randy Lerch | | 237 | 252 | -15 |
| 1980-06-22 | vs PHI | 66 | L 3-4 | 30-36 | 4 | 27,315 | Vida Blue | Steve Carlton | Steve Carlton | Vida Blue | | 240 | 256 | -16 |
| 1980-06-24 | @ SDN | 67 | L 3-5 | 30-37 | 4 | 10,772 | Bob Knepper | Eric Rasmussen | John D'Acquisto | Bob Knepper | | 243 | 261 | -18 |
| 1980-06-25 | @ SDN | 68 | L 3-7 | 30-38 | 5 | 11,336 | Allen Ripley | Juan Eichelberger | Juan Eichelberger | Allen Ripley | Rollie Fingers | 246 | 268 | -22 |
| 1980-06-26 | @ SDN | 69 | W 2-1 | 31-38 | 4 | 11,321 | Ed Whitson | Steve Mura | Ed Whitson | Steve Mura | Greg Minton | 248 | 269 | -21 |
| 1980-06-27 | vs LAN | 70 | L 0-8 | 31-39 | 4 | 20,285 | Vida Blue | Jerry Reuss | Jerry Reuss | Vida Blue | | 248 | 277 | -29 |
| 1980-06-28 | vs LAN | 71 | W 4-3 | 32-39 | 4 | 25,145 | John Montefusco | Dave Goltz | Tom Griffin | Rick Sutcliffe | | 252 | 280 | -28 |
| 1980-06-29 | vs LAN | 72 | W 4-3 | 33-40 | 4 | 0 | Bob Knepper | Don Sutton | Bob Knepper | Bobby Castillo | | 256 | 283 | -27 |
| 1980-06-29 | vs LAN | 73 | L 0-3 | 33-40 | 4 | 50,229 | Allen Ripley | Burt Hooton | Burt Hooton | Allen Ripley | | 256 | 286 | -30 |
| 1980-06-30 | vs CIN | 74 | W 8-4 | 34-40 | 4 | 5,716 | Bill Bordley | Tom Seaver | Bill Bordley | Tom Seaver | Gary Lavelle | 264 | 290 | -26 |
| 1980-07-01 | vs CIN | 75 | W 4-1 | 35-40 | 4 | 20,220 | Ed Whitson | Paul Moskau | Ed Whitson | Paul Moskau | | 268 | 291 | -23 |
| 1980-07-02 | vs CIN | 76 | L 2-6 | 35-41 | 5 | 10,459 | John Montefusco | Frank Pastore | Frank Pastore | John Montefusco | | 270 | 297 | -27 |
| 1980-07-03 | vs CIN | 77 | W 4-3 | 36-41 | 4 | 26,133 | Bob Knepper | Joe Price | Bob Knepper | Joe Price | Greg Minton | 274 | 300 | -26 |
| 1980-07-04 | @ LAN | 78 | L 0-4 | 36-42 | 5 | 49,846 | Allen Ripley | Don Sutton | Don Sutton | Allen Ripley | | 274 | 304 | -30 |
| 1980-07-05 | @ LAN | 79 | L 2-3 | 36-43 | 5 | 41,587 | Ed Whitson | Bob Welch | Bob Welch | Ed Whitson | Bobby Castillo | 276 | 307 | -31 |
| 1980-07-06 | @ LAN | 80 | W 7-4 | 37-43 | 5 | 46,244 | John Montefusco | Jerry Reuss | Al Holland | Steve Howe | | 283 | 311 | -28 |
| 1980-07-10 | vs SDN | 81 | W 9-2 | 38-43 | 5 | 8,175 | Bob Knepper | Randy Jones | Bob Knepper | Randy Jones | | 292 | 313 | -21 |
| 1980-07-11 | vs SDN | 82 | W 7-3 | 39-43 | 4 | 7,782 | Ed Whitson | John Curtis | Ed Whitson | John Curtis | | 299 | 316 | -17 |
| 1980-07-12 | @ CIN | 83 | W 7-4 | 41-43 | 4 | 0 | John Montefusco | Bruce Berenyi | Gary Lavelle | Doug Bair | Greg Minton | 306 | 320 | -14 |
| 1980-07-12 | @ CIN | 84 | W 10-7 | 41-43 | 4 | 35,584 | Bill Bordley | Mike LaCoss | Bill Bordley | Mike LaCoss | Greg Minton | 316 | 327 | -11 |
| 1980-07-13 | @ CIN | 85 | W 2-0 | 42-43 | 4 | 25,014 | Allen Ripley | Joe Price | Allen Ripley | Joe Price | Al Holland | 318 | 327 | -9 |
| 1980-07-14 | @ CIN | 86 | W 5-3 | 43-43 | 4 | 20,158 | Alan Hargesheimer | Charlie Leibrandt | Alan Hargesheimer | Charlie Leibrandt | Gary Lavelle | 323 | 330 | -7 |
| 1980-07-15 | @ PIT | 87 | L 2-5 | 43-44 | 4 | 17,114 | Bob Knepper | John Candelaria | John Candelaria | Bob Knepper | Kent Tekulve | 325 | 335 | -10 |
| 1980-07-16 | @ PIT | 88 | L 1-3 | 43-45 | 4 | 18,226 | Ed Whitson | Bert Blyleven | Bert Blyleven | Ed Whitson | Grant Jackson | 326 | 338 | -12 |
| 1980-07-17 | @ PIT | 89 | L 2-3 | 43-46 | 4 | 25,508 | Bill Bordley | Jim Bibby | Kent Tekulve | Al Holland | | 328 | 341 | -13 |
| 1980-07-18 | @ SLN | 90 | W 8-7 | 44-46 | 4 | 18,950 | Allen Ripley | Silvio Martinez | Al Holland | Kim Seaman | | 336 | 348 | -12 |
| 1980-07-19 | @ SLN | 91 | W 7-4 | 45-46 | 4 | 26,513 | Alan Hargesheimer | Bob Sykes | Alan Hargesheimer | Bob Sykes | Gary Lavelle | 343 | 352 | -9 |
| 1980-07-20 | @ SLN | 92 | L 1-2 | 45-47 | 4 | 30,271 | Bob Knepper | Bob Forsch | Bob Forsch | Bob Knepper | | 344 | 354 | -10 |
| 1980-07-21 | @ CHN | 93 | W 2-0 | 46-47 | 4 | 15,786 | Ed Whitson | Rick Reuschel | Gary Lavelle | Bill Caudill | | 346 | 354 | -8 |
| 1980-07-22 | @ CHN | 94 | L 1-3 | 46-48 | 4 | 17,150 | Bill Bordley | Dennis Lamp | Dennis Lamp | Bill Bordley | | 347 | 357 | -10 |
| 1980-07-23 | @ CHN | 95 | W 14-6 | 47-48 | 4 | 29,189 | Allen Ripley | Doug Capilla | Allen Ripley | Doug Capilla | | 361 | 363 | -2 |
| 1980-07-25 | vs PIT | 96 | L 1-5 | 47-49 | 4 | 22,830 | Bob Knepper | John Candelaria | John Candelaria | Bob Knepper | | 362 | 368 | -6 |
| 1980-07-26 | vs PIT | 97 | W 4-3 | 48-49 | 4 | 28,566 | Alan Hargesheimer | Eddie Solomon | Greg Minton | Grant Jackson | | 366 | 371 | -5 |
| 1980-07-27 | vs PIT | 98 | L 4-6 | 48-50 | 4 | 31,186 | Bill Bordley | Jim Bibby | Jim Bibby | Bill Bordley | Kent Tekulve | 370 | 377 | -7 |
| 1980-07-29 | vs SLN | 99 | W 4-1 | 49-50 | 4 | 22,991 | Allen Ripley | Silvio Martinez | Allen Ripley | Silvio Martinez | Greg Minton | 374 | 378 | -4 |
| 1980-07-30 | vs SLN | 100 | L 0-4 | 49-51 | 4 | 12,165 | Bob Knepper | John Fulgham | John Fulgham | Bob Knepper | | 374 | 382 | -8 |
| 1980-07-31 | vs SLN | 101 | W 6-4 | 50-51 | 4 | 9,982 | Alan Hargesheimer | Bob Sykes | Gary Lavelle | John Urrea | Al Holland | 380 | 386 | -6 |
| 1980-08-01 | vs CHN | 102 | L 3-5 | 50-52 | 4 | 12,389 | Bill Bordley | Rick Reuschel | Rick Reuschel | Bill Bordley | Bruce Sutter | 383 | 391 | -8 |
| 1980-08-02 | vs CHN | 103 | W 8-5 | 51-52 | 4 | 10,392 | Vida Blue | Dennis Lamp | Tom Griffin | Dick Tidrow | Greg Minton | 391 | 396 | -5 |
| 1980-08-03 | vs CHN | 104 | L 2-3 | 51-54 | 4 | 0 | Allen Ripley | Mike Krukow | Mike Krukow | Allen Ripley | | 393 | 399 | -6 |
| 1980-08-03 | vs CHN | 105 | L 2-3 | 51-54 | 4 | 28,497 | Bob Knepper | Bill Caudill | Dick Tidrow | Bob Knepper | Bruce Sutter | 395 | 402 | -7 |
| 1980-08-04 | @ HOU | 106 | L 2-4 | 51-55 | 4 | 27,040 | Alan Hargesheimer | Nolan Ryan | Nolan Ryan | Alan Hargesheimer | Joe Sambito | 397 | 406 | -9 |
| 1980-08-05 | @ HOU | 107 | W 9-3 | 52-55 | 4 | 24,198 | Jeff Stember | Gordie Pladson | Gary Lavelle | Gordie Pladson | | 406 | 409 | -3 |
| 1980-08-06 | @ HOU | 108 | L 0-1 | 52-56 | 4 | 23,478 | Vida Blue | Ken Forsch | Ken Forsch | Vida Blue | | 406 | 410 | -4 |
| 1980-08-08 | @ ATL | 109 | L 3-7 | 52-57 | 4 | 9,014 | Allen Ripley | Larry McWilliams | Larry McWilliams | Greg Minton | | 409 | 417 | -8 |
| 1980-08-09 | @ ATL | 110 | W 5-4 | 53-57 | 4 | 17,906 | Bob Knepper | Tommy Boggs | Al Holland | Tommy Boggs | Greg Minton | 414 | 421 | -7 |
| 1980-08-10 | @ ATL | 111 | L 1-3 | 53-58 | 4 | 9,027 | Alan Hargesheimer | Phil Niekro | Phil Niekro | Alan Hargesheimer | Rick Camp | 415 | 424 | -9 |
| 1980-08-11 | vs HOU | 112 | W 5-4 | 54-58 | 4 | 10,755 | Vida Blue | Ken Forsch | Vida Blue | Ken Forsch | Greg Minton | 420 | 428 | -8 |
| 1980-08-12 | vs HOU | 113 | W 2-0 | 55-58 | 4 | 29,770 | Allen Ripley | Joe Niekro | Allen Ripley | Joe Niekro | Gary Lavelle | 422 | 428 | -6 |
| 1980-08-13 | vs HOU | 114 | W 6-5 | 56-58 | 4 | 10,149 | Bob Knepper | Vern Ruhle | Mike Rowland | Dave Smith | | 428 | 433 | -5 |
| 1980-08-14 | vs ATL | 115 | W 5-1 | 57-58 | 4 | 5,448 | Alan Hargesheimer | Larry McWilliams | Alan Hargesheimer | Larry McWilliams | Greg Minton | 433 | 434 | -1 |
| 1980-08-15 | vs ATL | 116 | L 2-8 | 57-59 | 4 | 10,556 | Ed Whitson | Phil Niekro | Gene Garber | Gary Lavelle | | 435 | 442 | -7 |
| 1980-08-16 | vs ATL | 117 | W 2-1 | 58-59 | 4 | 14,634 | Vida Blue | Rick Matula | Vida Blue | Rick Matula | | 437 | 443 | -6 |
| 1980-08-17 | vs ATL | 118 | L 2-8 | 58-60 | 4 | 21,029 | Allen Ripley | Doyle Alexander | Doyle Alexander | Allen Ripley | | 439 | 451 | -12 |
| 1980-08-19 | @ NYN | 119 | W 5-4 | 59-60 | 4 | 13,871 | Bob Knepper | Pat Zachry | Bob Knepper | Jeff Reardon | Greg Minton | 444 | 455 | -11 |
| 1980-08-20 | @ NYN | 120 | W 2-1 | 60-60 | 4 | 13,488 | Alan Hargesheimer | Mark Bomback | Alan Hargesheimer | Mark Bomback | Greg Minton | 446 | 456 | -10 |
| 1980-08-21 | @ NYN | 121 | L 1-5 | 60-61 | 4 | 10,505 | Vida Blue | Craig Swan | Pete Falcone | Vida Blue | | 447 | 461 | -14 |
| 1980-08-22 | @ PHI | 122 | W 4-3 | 61-61 | 4 | 36,073 | Ed Whitson | Steve Carlton | Al Holland | Steve Carlton | | 451 | 464 | -13 |
| 1980-08-23 | @ PHI | 123 | W 6-2 | 62-61 | 4 | 38,541 | Allen Ripley | Larry Christenson | Allen Ripley | Larry Christenson | | 457 | 466 | -9 |
| 1980-08-24 | @ PHI | 124 | L 1-7 | 62-62 | 4 | 37,325 | Bob Knepper | Dick Ruthven | Dick Ruthven | Bob Knepper | | 458 | 473 | -15 |
| 1980-08-25 | @ MON | 125 | L 1-3 | 62-63 | 4 | 32,602 | Alan Hargesheimer | Steve Rogers | Steve Rogers | Alan Hargesheimer | | 459 | 476 | -17 |
| 1980-08-27 | @ MON | 126 | W 1-0 | 63-63 | 5 | 24,294 | Ed Whitson | Scott Sanderson | Ed Whitson | Scott Sanderson | Greg Minton | 460 | 476 | -16 |
| 1980-08-29 | vs NYN | 127 | W 1-0 | 64-63 | 4 | 9,269 | Vida Blue | Pat Zachry | Vida Blue | Pat Zachry | | 461 | 476 | -15 |
| 1980-08-30 | vs NYN | 128 | L 5-9 | 64-64 | 4 | 11,270 | Allen Ripley | Roy Lee Jackson | Tom Hausman | Allen Ripley | Jeff Reardon | 466 | 485 | -19 |
| 1980-08-31 | vs NYN | 129 | W 11-4 | 66-64 | 4 | 0 | Alan Hargesheimer | Pete Falcone | Gary Lavelle | Pete Falcone | Al Holland | 477 | 489 | -12 |
| 1980-08-31 | vs NYN | 130 | W 9-4 | 66-64 | 4 | 18,640 | Bob Knepper | Mark Bomback | John Montefusco | Dyar Miller | Greg Minton | 486 | 493 | -7 |
| 1980-09-01 | vs PHI | 131 | L 4-6 | 66-65 | 5 | 16,952 | Ed Whitson | Steve Carlton | Steve Carlton | Greg Minton | | 490 | 499 | -9 |
| 1980-09-02 | vs PHI | 132 | L 1-2 | 66-66 | 5 | 6,135 | Vida Blue | Larry Christenson | Ron Reed | Al Holland | | 491 | 501 | -10 |
| 1980-09-03 | vs PHI | 133 | L 3-4 | 66-67 | 5 | 5,504 | Allen Ripley | Dick Ruthven | Dick Ruthven | Allen Ripley | Tug McGraw | 494 | 505 | -11 |
| 1980-09-04 | vs MON | 134 | L 0-4 | 66-68 | 5 | 4,038 | Alan Hargesheimer | Bill Gullickson | Bill Gullickson | Alan Hargesheimer | | 494 | 509 | -15 |
| 1980-09-05 | vs MON | 135 | L 0-8 | 66-69 | 5 | 7,698 | John Montefusco | Steve Rogers | Steve Rogers | John Montefusco | | 494 | 517 | -23 |
| 1980-09-06 | vs MON | 136 | L 0-9 | 66-70 | 5 | 6,653 | Ed Whitson | Scott Sanderson | Scott Sanderson | Ed Whitson | | 494 | 526 | -32 |
| 1980-09-07 | vs MON | 137 | W 6-3 | 67-70 | 5 | 8,314 | Vida Blue | Charlie Lea | Vida Blue | John D'Acquisto | Greg Minton | 500 | 529 | -29 |
| 1980-09-09 | @ SDN | 138 | L 5-12 | 67-71 | 5 | 6,241 | Allen Ripley | Steve Mura | Steve Mura | Allen Ripley | | 505 | 541 | -36 |
| 1980-09-10 | @ SDN | 139 | L 2-4 | 67-72 | 5 | 6,834 | Bob Knepper | John Curtis | Rollie Fingers | Greg Minton | Gary Lucas | 507 | 545 | -38 |
| 1980-09-12 | @ HOU | 140 | L 3-5 | 67-73 | 5 | 23,380 | Ed Whitson | Joe Niekro | Joe Niekro | Ed Whitson | Dave Smith | 510 | 550 | -40 |
| 1980-09-13 | @ HOU | 141 | L 2-3 | 67-74 | 5 | 32,526 | Vida Blue | Ken Forsch | Ken Forsch | Vida Blue | | 512 | 553 | -41 |
| 1980-09-14 | @ HOU | 142 | L 4-6 | 67-75 | 5 | 18,471 | John Montefusco | Joaquin Andujar | Joaquin Andujar | John Montefusco | Joe Sambito | 516 | 559 | -43 |
| 1980-09-15 | @ CIN | 143 | L 2-6 | 67-76 | 5 | 16,002 | Bob Knepper | Tom Seaver | Tom Seaver | Bob Knepper | | 518 | 565 | -47 |
| 1980-09-16 | @ CIN | 144 | W 8-1 | 68-76 | 5 | 12,206 | Ed Whitson | Joe Price | Ed Whitson | Joe Price | | 526 | 566 | -40 |
| 1980-09-17 | vs ATL | 145 | W 2-0 | 69-76 | 5 | 2,164 | Vida Blue | Larry McWilliams | Vida Blue | Larry McWilliams | | 528 | 566 | -38 |
| 1980-09-18 | vs ATL | 146 | L 1-2 | 69-77 | 5 | 2,151 | Alan Hargesheimer | Rick Matula | Rick Matula | Alan Hargesheimer | Rick Camp | 529 | 568 | -39 |
| 1980-09-19 | vs HOU | 147 | W 4-3 | 70-77 | 5 | 4,377 | Tom Griffin | Joaquin Andujar | Tom Griffin | Joaquin Andujar | Al Holland | 533 | 571 | -38 |
| 1980-09-20 | vs HOU | 148 | L 2-3 | 70-78 | 5 | 16,770 | Ed Whitson | Nolan Ryan | Dave Smith | Gary Lavelle | Joe Sambito | 535 | 574 | -39 |
| 1980-09-21 | vs HOU | 149 | L 1-5 | 70-79 | 5 | 19,844 | Vida Blue | Vern Ruhle | Vern Ruhle | Vida Blue | | 536 | 579 | -43 |
| 1980-09-22 | vs CIN | 150 | W 7-3 | 71-79 | 5 | 3,003 | Allen Ripley | Mike LaCoss | Allen Ripley | Mike LaCoss | Gary Lavelle | 543 | 582 | -39 |
| 1980-09-23 | vs CIN | 151 | L 1-2 | 71-80 | 5 | 6,326 | Alan Hargesheimer | Frank Pastore | Frank Pastore | Alan Hargesheimer | | 544 | 584 | -40 |
| 1980-09-24 | @ LAN | 152 | L 4-5 | 71-81 | 5 | 35,581 | Tom Griffin | Jerry Reuss | Bobby Castillo | Mike Rowland | | 548 | 589 | -41 |
| 1980-09-25 | @ LAN | 153 | W 3-2 | 72-81 | 5 | 33,460 | Ed Whitson | Burt Hooton | Ed Whitson | Burt Hooton | Gary Lavelle | 551 | 591 | -40 |
| 1980-09-26 | @ ATL | 154 | L 3-5 | 72-82 | 5 | 6,578 | Vida Blue | Tommy Boggs | Tommy Boggs | Vida Blue | Rick Camp | 554 | 596 | -42 |
| 1980-09-27 | @ ATL | 155 | W 2-1 | 73-82 | 5 | 19,486 | Allen Ripley | Larry McWilliams | Allen Ripley | Larry McWilliams | Gary Lavelle | 556 | 597 | -41 |
| 1980-09-30 | vs LAN | 156 | L 3-6 | 73-83 | 5 | 10,953 | Tom Griffin | Jerry Reuss | Fernando Valenzuela | Gary Lavelle | | 559 | 603 | -44 |
| 1980-10-01 | vs LAN | 157 | L 4-8 | 73-84 | 5 | 11,307 | Ed Whitson | Burt Hooton | Burt Hooton | Ed Whitson | | 563 | 611 | -48 |
| 1980-10-02 | vs LAN | 158 | W 3-2 | 74-84 | 5 | 11,693 | Vida Blue | Dave Goltz | Greg Minton | Dave Goltz | Al Holland | 566 | 613 | -47 |
| 1980-10-03 | vs SDN | 159 | L 0-12 | 74-85 | 5 | 2,740 | Allen Ripley | Steve Mura | Steve Mura | Allen Ripley | | 566 | 625 | -59 |
| 1980-10-04 | vs SDN | 160 | W 4-2 | 75-85 | 5 | 3,194 | Tom Griffin | George Stablein | Tom Griffin | George Stablein | Greg Minton | 570 | 627 | -57 |
| 1980-10-05 | vs SDN | 161 | L 3-7 | 75-86 | 5 | 14,680 | Ed Whitson | Tom Tellmann | Tom Tellmann | Ed Whitson | | 573 | 634 | -61 |