| 1980-04-10 | @ OAK | 1 | W 9-7 | 1-0 | 1 | 24,415 | Jerry Koosman | Rick Langford | Doug Corbett | Steve McCatty | | 9 | 7 | 2 |
| 1980-04-11 | @ OAK | 2 | L 0-1 | 1-1 | 5 | 5,729 | Pete Redfern | Matt Keough | Matt Keough | Pete Redfern | | 9 | 8 | 1 |
| 1980-04-12 | @ OAK | 3 | W 6-0 | 2-1 | 4 | 5,783 | Geoff Zahn | Brian Kingman | Geoff Zahn | Brian Kingman | | 15 | 8 | 7 |
| 1980-04-13 | @ OAK | 4 | L 1-4 | 2-2 | 5 | 6,300 | Roger Erickson | Mike Norris | Mike Norris | Roger Erickson | | 16 | 12 | 4 |
| 1980-04-14 | @ CAL | 5 | W 5-3 | 3-2 | 4 | 24,944 | Terry Felton | Chris Knapp | Doug Corbett | Mark Clear | | 21 | 15 | 6 |
| 1980-04-15 | @ CAL | 6 | L 1-3 | 3-3 | 6 | 26,105 | Jerry Koosman | Frank Tanana | Frank Tanana | Jerry Koosman | | 22 | 18 | 4 |
| 1980-04-16 | @ CAL | 7 | L 1-2 | 3-4 | 7 | 27,575 | Pete Redfern | Dave Frost | Dave Frost | Mike Marshall | | 23 | 20 | 3 |
| 1980-04-17 | @ SEA | 8 | L 3-4 | 3-5 | 7 | 5,466 | Geoff Zahn | Rick Honeycutt | Rick Honeycutt | Geoff Zahn | | 26 | 24 | 2 |
| 1980-04-18 | @ SEA | 9 | L 1-3 | 3-7 | 7 | 0 | Roger Erickson | Floyd Bannister | Floyd Bannister | Roger Erickson | | 27 | 27 | 0 |
| 1980-04-18 | @ SEA | 10 | L 2-3 | 3-7 | 7 | 7,006 | Terry Felton | Gary Wheelock | Byron McLaughlin | Terry Felton | Shane Rawley | 29 | 30 | -1 |
| 1980-04-19 | @ SEA | 11 | W 8-3 | 4-7 | 7 | 11,151 | Jerry Koosman | Glenn Abbott | Jerry Koosman | Glenn Abbott | | 37 | 33 | 4 |
| 1980-04-20 | @ SEA | 12 | W 4-3 | 5-7 | 6 | 8,225 | Pete Redfern | Mike Parrott | Pete Redfern | Mike Parrott | Mike Marshall | 41 | 36 | 5 |
| 1980-04-22 | vs CAL | 13 | W 8-1 | 6-7 | 6 | 36,268 | Geoff Zahn | Dave Frost | Geoff Zahn | Dave Frost | | 49 | 37 | 12 |
| 1980-04-23 | vs CAL | 14 | L 0-17 | 6-8 | 6 | 4,772 | Terry Felton | Bruce Kison | Bruce Kison | Terry Felton | | 49 | 54 | -5 |
| 1980-04-25 | vs OAK | 15 | W 10-3 | 7-8 | 6 | 2,664 | Jerry Koosman | Matt Keough | Jerry Koosman | Matt Keough | | 59 | 57 | 2 |
| 1980-04-26 | vs OAK | 16 | W 5-1 | 8-8 | 5 | 6,325 | Pete Redfern | Steve McCatty | Pete Redfern | Steve McCatty | | 64 | 58 | 6 |
| 1980-04-27 | vs OAK | 17 | W 20-11 | 9-8 | 5 | 19,859 | Geoff Zahn | Brian Kingman | Doug Corbett | Brian Kingman | | 84 | 69 | 15 |
| 1980-04-28 | vs SEA | 18 | L 4-6 | 9-9 | 6 | 2,544 | Terry Felton | Rick Honeycutt | Rick Honeycutt | Terry Felton | Dave Heaverlo | 88 | 75 | 13 |
| 1980-04-29 | vs SEA | 19 | L 3-5 | 9-10 | 6 | 2,580 | Jerry Koosman | Floyd Bannister | Shane Rawley | Mike Marshall | | 91 | 80 | 11 |
| 1980-04-30 | vs SEA | 20 | W 10-3 | 10-10 | 6 | 2,891 | Pete Redfern | Mike Parrott | Pete Redfern | Mike Parrott | | 101 | 83 | 18 |
| 1980-05-02 | vs NYA | 21 | L 6-9 | 10-11 | 7 | 17,067 | Geoff Zahn | Ron Guidry | Ron Guidry | Geoff Zahn | Rudy May | 107 | 92 | 15 |
| 1980-05-03 | vs NYA | 22 | L 3-7 | 10-12 | 7 | 12,054 | Darrell Jackson | Tommy John | Tommy John | Darrell Jackson | | 110 | 99 | 11 |
| 1980-05-04 | vs NYA | 23 | L 1-10 | 10-13 | 7 | 13,085 | Jerry Koosman | Tom Underwood | Tom Underwood | Jerry Koosman | | 111 | 109 | 2 |
| 1980-05-05 | @ BAL | 24 | W 4-2 | 11-13 | 7 | 12,418 | Pete Redfern | Steve Stone | Pete Redfern | Steve Stone | Doug Corbett | 115 | 111 | 4 |
| 1980-05-06 | @ BAL | 25 | L 3-10 | 11-14 | 7 | 10,720 | Geoff Zahn | Scott McGregor | Scott McGregor | Geoff Zahn | | 118 | 121 | -3 |
| 1980-05-07 | @ BAL | 26 | L 6-8 | 11-15 | 7 | 11,357 | Albert Williams | Mike Flanagan | Sammy Stewart | Mike Marshall | Tippy Martinez | 124 | 129 | -5 |
| 1980-05-09 | @ NYA | 27 | L 2-5 | 11-16 | 7 | 27,225 | Jerry Koosman | Ron Guidry | Ron Guidry | Jerry Koosman | Rich Gossage | 126 | 134 | -8 |
| 1980-05-10 | @ NYA | 28 | W 1-0 | 12-16 | 6 | 28,015 | Darrell Jackson | Tom Underwood | Darrell Jackson | Rudy May | Doug Corbett | 127 | 134 | -7 |
| 1980-05-11 | @ NYA | 29 | L 0-5 | 12-17 | 6 | 30,680 | Geoff Zahn | Tommy John | Tommy John | Geoff Zahn | | 127 | 139 | -12 |
| 1980-05-12 | @ BOS | 30 | W 4-3 | 13-17 | 6 | 18,486 | Pete Redfern | Mike Torrez | Pete Redfern | Mike Torrez | Doug Corbett | 131 | 142 | -11 |
| 1980-05-13 | @ BOS | 31 | L 5-10 | 13-18 | 6 | 19,032 | Albert Williams | Bruce Hurst | Steve Renko | John Verhoeven | Tom Burgmeier | 136 | 152 | -16 |
| 1980-05-14 | @ BOS | 32 | L 6-7 | 13-19 | 7 | 24,590 | Jerry Koosman | Bob Stanley | Tom Burgmeier | Doug Corbett | | 142 | 159 | -17 |
| 1980-05-16 | vs MIL | 33 | W 4-3 | 14-19 | 7 | 12,331 | Darrell Jackson | Mike Caldwell | Jerry Koosman | Bob McClure | Doug Corbett | 146 | 162 | -16 |
| 1980-05-17 | vs MIL | 34 | L 11-14 | 14-20 | 7 | 13,394 | Geoff Zahn | John Flinn | Jerry Augustine | Geoff Zahn | Bill Castro | 157 | 176 | -19 |
| 1980-05-18 | vs MIL | 35 | W 10-4 | 15-20 | 6 | 17,929 | Pete Redfern | Bill Travers | Pete Redfern | Bill Travers | | 167 | 180 | -13 |
| 1980-05-19 | @ CHA | 36 | L 0-1 | 15-21 | 7 | 9,272 | Jerry Koosman | Ken Kravec | Ken Kravec | Jerry Koosman | Ed Farmer | 167 | 181 | -14 |
| 1980-05-20 | @ CHA | 37 | L 2-4 | 15-22 | 7 | 12,864 | Darrell Jackson | Richard Dotson | Richard Dotson | Darrell Jackson | Ed Farmer | 169 | 185 | -16 |
| 1980-05-21 | @ CHA | 38 | W 3-2 | 16-22 | 7 | 33,967 | Geoff Zahn | Steve Trout | Geoff Zahn | Steve Trout | | 172 | 187 | -15 |
| 1980-05-23 | @ MIL | 39 | L 0-5 | 16-23 | 7 | 14,322 | Pete Redfern | Bill Travers | Bill Travers | Pete Redfern | | 172 | 192 | -20 |
| 1980-05-24 | @ MIL | 40 | L 0-4 | 16-24 | 7 | 22,241 | Jerry Koosman | Moose Haas | Moose Haas | Jerry Koosman | | 172 | 196 | -24 |
| 1980-05-25 | @ MIL | 41 | L 2-3 | 16-25 | 7 | 31,895 | Roger Erickson | Lary Sorensen | Lary Sorensen | Roger Erickson | | 174 | 199 | -25 |
| 1980-05-26 | vs CHA | 42 | L 3-6 | 16-26 | 7 | 5,436 | Geoff Zahn | Steve Trout | Steve Trout | Geoff Zahn | Ed Farmer | 177 | 205 | -28 |
| 1980-05-27 | vs CHA | 43 | L 0-2 | 16-27 | 7 | 4,362 | Darrell Jackson | Britt Burns | Britt Burns | Darrell Jackson | Mike Proly | 177 | 207 | -30 |
| 1980-05-28 | vs CHA | 44 | W 6-4 | 17-27 | 7 | 4,256 | Pete Redfern | Ken Kravec | Mike Marshall | Mike Proly | | 183 | 211 | -28 |
| 1980-05-29 | vs CHA | 45 | W 5-2 | 18-27 | 7 | 5,204 | Jerry Koosman | Richard Dotson | Jerry Koosman | Richard Dotson | | 188 | 213 | -25 |
| 1980-05-30 | vs BAL | 46 | L 2-3 | 18-28 | 7 | 4,889 | Roger Erickson | Mike Flanagan | Mike Flanagan | Doug Corbett | Tippy Martinez | 190 | 216 | -26 |
| 1980-05-31 | vs BAL | 47 | L 1-11 | 18-29 | 7 | 8,288 | Geoff Zahn | Scott McGregor | Scott McGregor | Geoff Zahn | | 191 | 227 | -36 |
| 1980-06-02 | vs BOS | 48 | L 2-6 | 18-30 | 7 | 6,322 | Pete Redfern | Bob Stanley | Bob Stanley | Pete Redfern | | 193 | 233 | -40 |
| 1980-06-03 | vs BOS | 49 | W 9-4 | 19-30 | 7 | 8,346 | Jerry Koosman | Jack Billingham | Jerry Koosman | Jack Billingham | | 202 | 237 | -35 |
| 1980-06-06 | vs TOR | 50 | W 5-0 | 20-30 | 7 | 5,495 | Geoff Zahn | Paul Mirabella | Geoff Zahn | Paul Mirabella | | 207 | 237 | -30 |
| 1980-06-07 | vs TOR | 51 | W 3-2 | 21-30 | 6 | 5,375 | Darrell Jackson | Dave Stieb | Darrell Jackson | Dave Stieb | Doug Corbett | 210 | 239 | -29 |
| 1980-06-08 | vs TOR | 52 | W 5-1 | 22-31 | 6 | 0 | Roger Erickson | Jesse Jefferson | Roger Erickson | Jesse Jefferson | Doug Corbett | 215 | 240 | -25 |
| 1980-06-08 | vs TOR | 53 | L 4-6 | 22-31 | 6 | 17,869 | Jerry Koosman | Luis Leal | Joey McLaughlin | Fernando Arroyo | | 219 | 246 | -27 |
| 1980-06-10 | @ DET | 54 | L 3-8 | 22-32 | 6 | 12,399 | Geoff Zahn | Milt Wilcox | Milt Wilcox | Geoff Zahn | | 222 | 254 | -32 |
| 1980-06-11 | @ DET | 55 | W 9-5 | 23-32 | 6 | 16,017 | Darrell Jackson | Dave Rozema | Darrell Jackson | Dave Rozema | Jerry Koosman | 231 | 259 | -28 |
| 1980-06-12 | @ DET | 56 | L 4-8 | 23-33 | 6 | 15,630 | Pete Redfern | Pat Underwood | Pat Underwood | Geoff Zahn | Aurelio Lopez | 235 | 267 | -32 |
| 1980-06-13 | @ CLE | 57 | L 2-6 | 23-34 | 6 | 11,336 | Jerry Koosman | John Denny | John Denny | Jerry Koosman | | 237 | 273 | -36 |
| 1980-06-14 | @ CLE | 58 | L 2-3 | 23-35 | 6 | 12,948 | Roger Erickson | Len Barker | Len Barker | Roger Erickson | | 239 | 276 | -37 |
| 1980-06-15 | @ CLE | 59 | L 5-14 | 23-36 | 6 | 25,182 | Darrell Jackson | Dan Spillner | Dan Spillner | Darrell Jackson | | 244 | 290 | -46 |
| 1980-06-16 | @ TOR | 60 | W 4-0 | 24-36 | 6 | 14,691 | Geoff Zahn | Jesse Jefferson | Geoff Zahn | Jesse Jefferson | | 248 | 290 | -42 |
| 1980-06-17 | @ TOR | 61 | W 8-6 | 25-36 | 6 | 15,229 | Pete Redfern | Paul Mirabella | Doug Corbett | Paul Mirabella | | 256 | 296 | -40 |
| 1980-06-19 | vs DET | 62 | W 5-1 | 26-36 | 6 | 14,704 | Darrell Jackson | Dan Schatzeder | Darrell Jackson | Dan Schatzeder | | 261 | 297 | -36 |
| 1980-06-20 | vs CLE | 63 | L 3-4 | 26-37 | 6 | 7,668 | Roger Erickson | Dan Spillner | Victor Cruz | Pete Redfern | Mike Stanton | 264 | 301 | -37 |
| 1980-06-21 | vs CLE | 64 | W 3-2 | 27-37 | 6 | 7,665 | Geoff Zahn | Wayne Garland | Geoff Zahn | Wayne Garland | Darrell Jackson | 267 | 303 | -36 |
| 1980-06-22 | vs CLE | 65 | L 6-11 | 27-38 | 6 | 9,676 | Pete Redfern | Rick Waits | Rick Waits | Pete Redfern | | 273 | 314 | -41 |
| 1980-06-23 | vs KCA | 66 | W 4-1 | 28-38 | 6 | 7,525 | Jerry Koosman | Larry Gura | Jerry Koosman | Larry Gura | | 277 | 315 | -38 |
| 1980-06-24 | vs KCA | 67 | W 2-1 | 29-39 | 6 | 0 | Darrell Jackson | Dennis Leonard | Darrell Jackson | Dan Quisenberry | | 279 | 316 | -37 |
| 1980-06-24 | vs KCA | 68 | L 2-4 | 29-39 | 6 | 11,556 | Roger Erickson | Renie Martin | Renie Martin | Roger Erickson | Dan Quisenberry | 281 | 320 | -39 |
| 1980-06-25 | vs KCA | 69 | L 1-4 | 29-40 | 6 | 9,150 | Geoff Zahn | Paul Splittorff | Paul Splittorff | Geoff Zahn | Dan Quisenberry | 282 | 324 | -42 |
| 1980-06-27 | @ TEX | 70 | L 0-5 | 29-41 | 6 | 10,818 | Pete Redfern | Gaylord Perry | Gaylord Perry | Pete Redfern | | 282 | 329 | -47 |
| 1980-06-28 | @ TEX | 71 | L 3-11 | 29-42 | 6 | 14,336 | Jerry Koosman | Steve Comer | Steve Comer | Jerry Koosman | Danny Darwin | 285 | 340 | -55 |
| 1980-06-29 | @ TEX | 72 | W 5-3 | 30-42 | 6 | 22,342 | Roger Erickson | Doc Medich | Roger Erickson | Doc Medich | Doug Corbett | 290 | 343 | -53 |
| 1980-06-30 | @ KCA | 73 | W 12-3 | 31-42 | 6 | 33,540 | Darrell Jackson | Renie Martin | Darrell Jackson | Renie Martin | | 302 | 346 | -44 |
| 1980-07-01 | @ KCA | 74 | W 2-1 | 32-42 | 5 | 20,224 | Geoff Zahn | Paul Splittorff | Doug Corbett | Paul Splittorff | | 304 | 347 | -43 |
| 1980-07-02 | @ KCA | 75 | L 3-4 | 32-43 | 6 | 26,225 | Jerry Koosman | Rich Gale | Dan Quisenberry | Jerry Koosman | | 307 | 351 | -44 |
| 1980-07-03 | vs TEX | 76 | W 10-3 | 33-43 | 6 | 7,612 | Roger Erickson | Steve Comer | Roger Erickson | Steve Comer | Doug Corbett | 317 | 354 | -37 |
| 1980-07-04 | vs TEX | 77 | L 3-4 | 33-44 | 6 | 32,948 | Darrell Jackson | Doc Medich | Danny Darwin | John Verhoeven | | 320 | 358 | -38 |
| 1980-07-05 | vs TEX | 78 | W 2-1 | 34-44 | 5 | 9,398 | Geoff Zahn | Fergie Jenkins | Geoff Zahn | Fergie Jenkins | | 322 | 359 | -37 |
| 1980-07-06 | vs TEX | 79 | W 4-1 | 35-44 | 5 | 9,614 | Fernando Arroyo | Jon Matlack | Fernando Arroyo | Jon Matlack | Jerry Koosman | 326 | 360 | -34 |
| 1980-07-10 | @ SEA | 80 | W 12-4 | 36-44 | 4 | 9,051 | Jerry Koosman | Rick Honeycutt | Jerry Koosman | Rick Honeycutt | | 338 | 364 | -26 |
| 1980-07-11 | @ SEA | 81 | W 6-3 | 37-44 | 4 | 7,688 | Darrell Jackson | Glenn Abbott | Darrell Jackson | Glenn Abbott | Doug Corbett | 344 | 367 | -23 |
| 1980-07-12 | vs SEA | 82 | W 8-3 | 38-44 | 3 | 14,963 | Geoff Zahn | Floyd Bannister | Geoff Zahn | Floyd Bannister | | 352 | 370 | -18 |
| 1980-07-13 | vs SEA | 83 | W 7-6 | 39-44 | 3 | 8,573 | Roger Erickson | Jim Beattie | Doug Corbett | Shane Rawley | | 359 | 376 | -17 |
| 1980-07-14 | vs SEA | 84 | L 5-8 | 39-45 | 4 | 11,060 | Fernando Arroyo | Rick Honeycutt | Rick Honeycutt | Fernando Arroyo | Dave Roberts | 364 | 384 | -20 |
| 1980-07-15 | @ NYA | 85 | W 5-4 | 40-45 | 3 | 30,747 | Jerry Koosman | Ron Guidry | Jerry Koosman | Ron Guidry | Doug Corbett | 369 | 388 | -19 |
| 1980-07-16 | @ NYA | 86 | L 1-11 | 40-46 | 4 | 28,005 | Darrell Jackson | Tom Underwood | Tom Underwood | Darrell Jackson | | 370 | 399 | -29 |
| 1980-07-17 | @ NYA | 87 | L 3-10 | 40-47 | 5 | 25,035 | Geoff Zahn | Tommy John | Tommy John | Geoff Zahn | | 373 | 409 | -36 |
| 1980-07-18 | @ BOS | 88 | L 0-1 | 40-48 | 5 | 28,116 | Roger Erickson | Mike Torrez | Mike Torrez | Roger Erickson | | 373 | 410 | -37 |
| 1980-07-19 | @ BOS | 89 | W 4-0 | 41-48 | 5 | 32,820 | Fernando Arroyo | Bob Ojeda | Fernando Arroyo | Bob Ojeda | | 377 | 410 | -33 |
| 1980-07-20 | @ BOS | 90 | W 5-4 | 42-48 | 4 | 28,493 | Jerry Koosman | Steve Renko | Doug Corbett | Dick Drago | | 382 | 414 | -32 |
| 1980-07-21 | vs BAL | 91 | W 8-7 | 43-49 | 4 | 0 | Darrell Jackson | Dennis Martinez | John Verhoeven | Tippy Martinez | | 390 | 421 | -31 |
| 1980-07-21 | vs BAL | 92 | L 5-12 | 43-49 | 4 | 15,373 | Geoff Zahn | Steve Stone | Steve Stone | Geoff Zahn | | 395 | 433 | -38 |
| 1980-07-22 | vs BAL | 93 | L 4-8 | 43-50 | 5 | 11,554 | Roger Erickson | Mike Flanagan | Mike Flanagan | Roger Erickson | | 399 | 441 | -42 |
| 1980-07-23 | vs BAL | 94 | L 7-8 | 43-51 | 5 | 10,793 | Fernando Arroyo | Scott McGregor | Scott McGregor | Fernando Arroyo | Tippy Martinez | 406 | 449 | -43 |
| 1980-07-25 | vs BOS | 95 | L 5-7 | 44-52 | 4 | 0 | Jerry Koosman | Bob Ojeda | Win Remmerswaal | Jerry Koosman | Tom Burgmeier | 411 | 456 | -45 |
| 1980-07-25 | vs BOS | 96 | W 6-0 | 44-52 | 4 | 23,998 | Geoff Zahn | Steve Renko | Geoff Zahn | Steve Renko | | 417 | 456 | -39 |
| 1980-07-26 | vs BOS | 97 | L 1-5 | 44-53 | 5 | 18,961 | Roger Erickson | Dennis Eckersley | Dennis Eckersley | Roger Erickson | | 418 | 461 | -43 |
| 1980-07-27 | vs BOS | 98 | W 5-4 | 45-53 | 5 | 26,008 | Fernando Arroyo | Mike Torrez | Albert Williams | Mike Torrez | Doug Corbett | 423 | 465 | -42 |
| 1980-07-28 | vs NYA | 99 | L 6-7 | 45-54 | 5 | 23,182 | Darrell Jackson | Rudy May | Doug Bird | John Verhoeven | | 429 | 472 | -43 |
| 1980-07-29 | vs NYA | 100 | W 3-2 | 46-54 | 4 | 26,501 | Geoff Zahn | Luis Tiant | Geoff Zahn | Luis Tiant | | 432 | 474 | -42 |
| 1980-07-30 | vs NYA | 101 | W 2-1 | 47-54 | 4 | 27,020 | Jerry Koosman | Tom Underwood | Jerry Koosman | Rich Gossage | | 434 | 475 | -41 |
| 1980-08-01 | @ BAL | 102 | L 2-3 | 47-55 | 4 | 21,839 | Roger Erickson | Mike Flanagan | Mike Flanagan | Doug Corbett | | 436 | 478 | -42 |
| 1980-08-02 | @ BAL | 103 | L 2-9 | 47-56 | 4 | 21,981 | Fernando Arroyo | Scott McGregor | Scott McGregor | Fernando Arroyo | | 438 | 487 | -49 |
| 1980-08-03 | @ BAL | 104 | L 2-7 | 47-57 | 5 | 16,526 | Darrell Jackson | Jim Palmer | Jim Palmer | Darrell Jackson | Tim Stoddard | 440 | 494 | -54 |
| 1980-08-04 | @ OAK | 105 | L 2-11 | 47-58 | 5 | 16,741 | Geoff Zahn | Steve McCatty | Steve McCatty | Geoff Zahn | | 442 | 505 | -63 |
| 1980-08-05 | @ OAK | 106 | L 2-3 | 47-59 | 5 | 4,651 | Jerry Koosman | Rick Langford | Rick Langford | Jerry Koosman | | 444 | 508 | -64 |
| 1980-08-06 | @ OAK | 107 | L 1-3 | 47-60 | 5 | 6,697 | Roger Erickson | Brian Kingman | Brian Kingman | Roger Erickson | | 445 | 511 | -66 |
| 1980-08-07 | @ CAL | 108 | L 2-4 | 47-61 | 5 | 24,195 | Fernando Arroyo | Dave LaRoche | Andy Hassler | Albert Williams | | 447 | 515 | -68 |
| 1980-08-08 | @ CAL | 109 | L 5-9 | 47-62 | 5 | 25,373 | Darrell Jackson | Alfredo Martinez | Dave Lemanczyk | Darrell Jackson | John Montague | 452 | 524 | -72 |
| 1980-08-09 | @ CAL | 110 | L 2-8 | 47-63 | 5 | 32,560 | Geoff Zahn | Frank Tanana | Frank Tanana | Geoff Zahn | | 454 | 532 | -78 |
| 1980-08-10 | @ CAL | 111 | W 5-2 | 48-63 | 5 | 23,007 | Jerry Koosman | Jim Barr | Jerry Koosman | Jim Barr | Doug Corbett | 459 | 534 | -75 |
| 1980-08-12 | vs OAK | 112 | W 3-2 | 49-63 | 4 | 13,181 | Roger Erickson | Brian Kingman | Doug Corbett | Brian Kingman | | 462 | 536 | -74 |
| 1980-08-13 | vs OAK | 113 | L 2-6 | 49-64 | 5 | 11,615 | Fernando Arroyo | Matt Keough | Matt Keough | Fernando Arroyo | | 464 | 542 | -78 |
| 1980-08-14 | vs OAK | 114 | L 1-2 | 49-65 | 5 | 13,077 | Darrell Jackson | Mike Norris | Mike Norris | Doug Corbett | | 465 | 544 | -79 |
| 1980-08-15 | vs CAL | 115 | L 4-5 | 49-66 | 5 | 14,685 | Geoff Zahn | Frank Tanana | Frank Tanana | Geoff Zahn | Andy Hassler | 469 | 549 | -80 |
| 1980-08-17 | vs CAL | 116 | W 8-1 | 51-66 | 4 | 0 | Roger Erickson | Jim Barr | Roger Erickson | Jim Barr | | 477 | 550 | -73 |
| 1980-08-17 | vs CAL | 117 | W 6-5 | 51-66 | 4 | 16,400 | Jerry Koosman | Chris Knapp | Jerry Koosman | Chris Knapp | Doug Corbett | 483 | 555 | -72 |
| 1980-08-18 | vs CAL | 118 | W 8-3 | 52-66 | 4 | 2,508 | Fernando Arroyo | Dave LaRoche | Fernando Arroyo | Dave LaRoche | | 491 | 558 | -67 |
| 1980-08-19 | vs TOR | 119 | L 3-4 | 52-67 | 4 | 6,902 | Darrell Jackson | Dave Stieb | Mike Barlow | Doug Corbett | Ken Schrom | 494 | 562 | -68 |
| 1980-08-20 | vs TOR | 120 | L 4-10 | 52-68 | 4 | 4,198 | Geoff Zahn | Jackson Todd | Jackson Todd | Geoff Zahn | | 498 | 572 | -74 |
| 1980-08-21 | vs DET | 121 | W 5-3 | 53-69 | 4 | 0 | Albert Williams | Milt Wilcox | Albert Williams | Milt Wilcox | Doug Corbett | 503 | 575 | -72 |
| 1980-08-21 | vs DET | 122 | L 2-4 | 53-69 | 4 | 8,687 | Roger Erickson | Jack Morris | Jack Morris | Roger Erickson | | 505 | 579 | -74 |
| 1980-08-22 | vs DET | 123 | W 6-5 | 54-69 | 4 | 12,473 | Jerry Koosman | Mark Fidrych | Fernando Arroyo | Dave Rozema | | 511 | 584 | -73 |
| 1980-08-23 | vs DET | 124 | L 3-4 | 54-70 | 5 | 7,062 | Darrell Jackson | Dan Petry | Bruce Robbins | Darrell Jackson | Dave Rozema | 514 | 588 | -74 |
| 1980-08-24 | vs DET | 125 | L 2-3 | 54-71 | 5 | 11,859 | Geoff Zahn | Dan Schatzeder | Dan Schatzeder | Geoff Zahn | | 516 | 591 | -75 |
| 1980-08-25 | @ CLE | 126 | L 3-4 | 54-72 | 5 | 14,211 | Fernando Arroyo | Dan Spillner | Dan Spillner | Fernando Arroyo | Sid Monge | 519 | 595 | -76 |
| 1980-08-26 | @ CLE | 127 | W 5-1 | 55-72 | 5 | 6,483 | Roger Erickson | Rick Waits | Roger Erickson | Rick Waits | | 524 | 596 | -72 |
| 1980-08-27 | @ CLE | 128 | L 1-4 | 55-73 | 5 | 7,572 | Jerry Koosman | Len Barker | Len Barker | Jerry Koosman | Victor Cruz | 525 | 600 | -75 |
| 1980-08-28 | @ TOR | 129 | W 7-5 | 56-73 | 5 | 14,035 | Darrell Jackson | Joey McLaughlin | John Verhoeven | Jesse Jefferson | Albert Williams | 532 | 605 | -73 |
| 1980-08-29 | @ TOR | 130 | W 5-2 | 57-73 | 4 | 14,358 | Geoff Zahn | Dave Stieb | Geoff Zahn | Dave Stieb | | 537 | 607 | -70 |
| 1980-08-30 | @ TOR | 131 | L 2-3 | 57-74 | 4 | 18,376 | Roger Erickson | Jackson Todd | Jackson Todd | John Verhoeven | | 539 | 610 | -71 |
| 1980-08-31 | @ TOR | 132 | L 1-7 | 57-75 | 5 | 18,029 | Jerry Koosman | Jim Clancy | Jim Clancy | Jerry Koosman | | 540 | 617 | -77 |
| 1980-09-01 | vs CLE | 133 | L 2-5 | 57-76 | 5 | 4,304 | Albert Williams | Len Barker | Len Barker | Albert Williams | | 542 | 622 | -80 |
| 1980-09-02 | vs CLE | 134 | W 5-3 | 58-76 | 5 | 2,934 | Darrell Jackson | Wayne Garland | Darrell Jackson | Wayne Garland | Doug Corbett | 547 | 625 | -78 |
| 1980-09-03 | vs CLE | 135 | L 1-7 | 58-77 | 5 | 2,877 | Geoff Zahn | Dan Spillner | Dan Spillner | Geoff Zahn | | 548 | 632 | -84 |
| 1980-09-05 | @ DET | 136 | L 0-1 | 58-78 | 5 | 16,980 | Roger Erickson | Dan Schatzeder | Dan Schatzeder | Roger Erickson | | 548 | 633 | -85 |
| 1980-09-06 | @ DET | 137 | W 4-0 | 59-78 | 5 | 18,249 | Jerry Koosman | Jack Morris | Jerry Koosman | Jack Morris | Doug Corbett | 552 | 633 | -81 |
| 1980-09-07 | @ DET | 138 | W 3-1 | 60-78 | 4 | 20,009 | Darrell Jackson | Mark Fidrych | Darrell Jackson | Mark Fidrych | Doug Corbett | 555 | 634 | -79 |
| 1980-09-09 | vs MIL | 139 | W 15-2 | 61-78 | 4 | 6,348 | Albert Williams | Lary Sorensen | Albert Williams | Lary Sorensen | | 570 | 636 | -66 |
| 1980-09-10 | vs MIL | 140 | L 1-3 | 61-79 | 5 | 6,722 | Roger Erickson | Paul Mitchell | Paul Mitchell | Roger Erickson | Dave LaPoint | 571 | 639 | -68 |
| 1980-09-12 | @ CHA | 141 | L 3-5 | 61-80 | 5 | 10,161 | Jerry Koosman | Britt Burns | Britt Burns | Jerry Koosman | Ed Farmer | 574 | 644 | -70 |
| 1980-09-13 | @ CHA | 142 | W 6-5 | 62-80 | 5 | 7,988 | Geoff Zahn | Steve Trout | Geoff Zahn | Steve Trout | Doug Corbett | 580 | 649 | -69 |
| 1980-09-14 | @ CHA | 143 | W 3-2 | 63-80 | 4 | 11,288 | Albert Williams | Ross Baumgarten | Fernando Arroyo | Ross Baumgarten | Doug Corbett | 583 | 651 | -68 |
| 1980-09-17 | @ MIL | 144 | W 3-2 | 65-80 | 4 | 0 | Jerry Koosman | Moose Haas | Jerry Koosman | Moose Haas | | 586 | 653 | -67 |
| 1980-09-17 | @ MIL | 145 | W 6-1 | 65-80 | 4 | 6,980 | Roger Erickson | Paul Mitchell | Roger Erickson | Paul Mitchell | | 592 | 654 | -62 |
| 1980-09-18 | @ MIL | 146 | L 8-9 | 65-82 | 4 | 0 | Geoff Zahn | Mike Caldwell | John Flinn | Doug Corbett | | 600 | 663 | -63 |
| 1980-09-18 | @ MIL | 147 | L 0-5 | 65-82 | 4 | 6,039 | Pete Redfern | Lary Sorensen | Lary Sorensen | Pete Redfern | | 600 | 668 | -68 |
| 1980-09-19 | vs CHA | 148 | W 6-3 | 66-82 | 4 | 2,911 | Albert Williams | Ross Baumgarten | Albert Williams | Ed Farmer | Doug Corbett | 606 | 671 | -65 |
| 1980-09-21 | vs CHA | 149 | W 5-4 | 68-82 | 4 | 0 | Geoff Zahn | LaMarr Hoyt | John Verhoeven | Dewey Robinson | | 611 | 675 | -64 |
| 1980-09-21 | vs CHA | 150 | W 6-4 | 68-82 | 4 | 4,066 | Fernando Arroyo | Richard Dotson | Fernando Arroyo | Richard Dotson | Pete Redfern | 617 | 679 | -62 |
| 1980-09-22 | vs TEX | 151 | W 1-0 | 69-82 | 4 | 2,377 | Jerry Koosman | John Butcher | Jerry Koosman | John Butcher | Doug Corbett | 618 | 679 | -61 |
| 1980-09-23 | vs TEX | 152 | W 8-2 | 70-82 | 4 | 2,427 | Roger Erickson | Ken Clay | Roger Erickson | Ken Clay | Pete Redfern | 626 | 681 | -55 |
| 1980-09-24 | vs TEX | 153 | W 9-5 | 71-82 | 3 | 2,863 | Albert Williams | Jon Matlack | Albert Williams | Jon Matlack | | 635 | 686 | -51 |
| 1980-09-26 | vs KCA | 154 | W 3-0 | 72-82 | 3 | 9,837 | Geoff Zahn | Dennis Leonard | Geoff Zahn | Dennis Leonard | | 638 | 686 | -48 |
| 1980-09-27 | vs KCA | 155 | W 8-3 | 73-82 | 3 | 6,848 | Jerry Koosman | Larry Gura | Jerry Koosman | Larry Gura | | 646 | 689 | -43 |
| 1980-09-28 | vs KCA | 156 | W 8-7 | 74-82 | 3 | 6,938 | Roger Erickson | Paul Splittorff | Pete Redfern | Rich Gale | Doug Corbett | 654 | 696 | -42 |
| 1980-10-02 | @ TEX | 157 | W 6-3 | 76-82 | 3 | 0 | Geoff Zahn | Jon Matlack | Geoff Zahn | Jon Matlack | | 660 | 699 | -39 |
| 1980-10-02 | @ TEX | 158 | W 4-1 | 76-82 | 3 | 8,022 | Albert Williams | Fergie Jenkins | Albert Williams | Fergie Jenkins | | 664 | 700 | -36 |
| 1980-10-03 | @ KCA | 159 | W 5-3 | 77-82 | 3 | 20,714 | Jerry Koosman | Larry Gura | Jerry Koosman | Larry Gura | Doug Corbett | 669 | 703 | -34 |
| 1980-10-04 | @ KCA | 160 | L 1-17 | 77-83 | 3 | 23,751 | Roger Erickson | Dennis Leonard | Dennis Leonard | Roger Erickson | | 670 | 720 | -50 |
| 1980-10-05 | @ KCA | 161 | L 0-4 | 77-84 | 3 | 25,603 | Darrell Jackson | Paul Splittorff | Paul Splittorff | Darrell Jackson | Rich Gale | 670 | 724 | -54 |