| 1980-04-10 | @ KCA | 1 | W 5-1 | 1-0 | 2 | 34,901 | Jack Morris | Dennis Leonard | Jack Morris | Dennis Leonard | | 5 | 1 | 4 |
| 1980-04-11 | @ KCA | 2 | L 0-4 | 1-1 | 3 | 14,605 | Dan Schatzeder | Larry Gura | Larry Gura | Dan Schatzeder | | 5 | 5 | 0 |
| 1980-04-12 | @ KCA | 3 | L 6-8 | 1-2 | 4 | 16,130 | Milt Wilcox | Rich Gale | Marty Pattin | Pat Underwood | | 11 | 13 | -2 |
| 1980-04-13 | @ KCA | 4 | L 2-3 | 1-3 | 6 | 17,720 | Dave Rozema | Paul Splittorff | Paul Splittorff | Dave Rozema | Gary Christenson | 13 | 16 | -3 |
| 1980-04-14 | @ BOS | 5 | L 1-3 | 1-4 | 7 | 33,512 | Jack Morris | Dennis Eckersley | Dennis Eckersley | Jack Morris | Tom Burgmeier | 14 | 19 | -5 |
| 1980-04-16 | @ BOS | 6 | L 9-10 | 1-5 | 7 | 9,238 | Dan Schatzeder | Bruce Hurst | Steve Renko | Dan Schatzeder | Tom Burgmeier | 23 | 29 | -6 |
| 1980-04-17 | @ BOS | 7 | L 4-5 | 1-6 | 7 | 8,626 | Milt Wilcox | Mike Torrez | Dick Drago | Aurelio Lopez | | 27 | 34 | -7 |
| 1980-04-18 | vs KCA | 8 | L 6-9 | 1-7 | 7 | 50,687 | Dave Rozema | Paul Splittorff | Dan Quisenberry | Aurelio Lopez | | 33 | 43 | -10 |
| 1980-04-19 | vs KCA | 9 | W 8-6 | 2-7 | 7 | 13,583 | Jack Morris | Dennis Leonard | Jack Morris | Renie Martin | | 41 | 49 | -8 |
| 1980-04-20 | vs KCA | 10 | L 6-9 | 2-8 | 7 | 18,755 | Dan Schatzeder | Larry Gura | Renie Martin | Dan Schatzeder | Dan Quisenberry | 47 | 58 | -11 |
| 1980-04-21 | @ TEX | 11 | L 2-3 | 2-9 | 7 | 14,834 | Milt Wilcox | Jon Matlack | Jon Matlack | Milt Wilcox | Sparky Lyle | 49 | 61 | -12 |
| 1980-04-22 | @ TEX | 12 | W 2-0 | 3-9 | 6 | 14,650 | Dave Rozema | Fergie Jenkins | Dave Rozema | Fergie Jenkins | | 51 | 61 | -10 |
| 1980-04-23 | @ TEX | 13 | W 5-4 | 4-9 | 6 | 13,334 | Jack Morris | Steve Comer | Jack Morris | Steve Comer | Aurelio Lopez | 56 | 65 | -9 |
| 1980-04-25 | vs BOS | 14 | W 11-3 | 5-9 | 6 | 11,581 | Dan Schatzeder | Dennis Eckersley | Dan Schatzeder | Dennis Eckersley | | 67 | 68 | -1 |
| 1980-04-26 | vs BOS | 15 | L 7-12 | 5-10 | 6 | 20,261 | Milt Wilcox | Bruce Hurst | Bruce Hurst | Milt Wilcox | Tom Burgmeier | 74 | 80 | -6 |
| 1980-04-27 | vs BOS | 16 | W 8-5 | 6-10 | 6 | 16,882 | Dave Rozema | Mike Torrez | Dave Rozema | Mike Torrez | Aurelio Lopez | 82 | 85 | -3 |
| 1980-04-29 | vs TEX | 17 | L 5-10 | 6-11 | 6 | 7,941 | Jack Morris | Steve Comer | Steve Comer | Jack Morris | Dave Rajsich | 87 | 95 | -8 |
| 1980-04-30 | vs TEX | 18 | W 5-4 | 7-11 | 6 | 8,056 | Dan Schatzeder | Gaylord Perry | Milt Wilcox | Sparky Lyle | | 92 | 99 | -7 |
| 1980-05-02 | @ OAK | 19 | L 6-10 | 7-12 | 7 | 8,636 | Dave Rozema | Steve McCatty | Steve McCatty | Dave Rozema | | 98 | 109 | -11 |
| 1980-05-03 | @ OAK | 20 | L 3-5 | 7-13 | 7 | 7,062 | Jack Morris | Brian Kingman | Brian Kingman | Jack Morris | Jeff Jones | 101 | 114 | -13 |
| 1980-05-04 | @ OAK | 21 | W 4-0 | 8-14 | 6 | 0 | Milt Wilcox | Rick Langford | Milt Wilcox | Rick Langford | | 105 | 114 | -9 |
| 1980-05-04 | @ OAK | 22 | L 0-1 | 8-14 | 6 | 18,217 | Dan Schatzeder | Mike Norris | Mike Norris | Dan Schatzeder | | 105 | 115 | -10 |
| 1980-05-06 | @ SEA | 23 | W 9-5 | 9-14 | 6 | 5,821 | Dan Petry | Jim Beattie | Dan Petry | Jim Beattie | Aurelio Lopez | 114 | 120 | -6 |
| 1980-05-07 | @ SEA | 24 | L 6-7 | 9-15 | 7 | 4,934 | Dave Rozema | Glenn Abbott | Dave Heaverlo | Pat Underwood | | 120 | 127 | -7 |
| 1980-05-08 | @ SEA | 25 | L 3-4 | 9-16 | 7 | 6,950 | Jack Morris | Rick Honeycutt | Rick Honeycutt | Jack Morris | | 123 | 131 | -8 |
| 1980-05-09 | @ CAL | 26 | W 6-5 | 10-16 | 7 | 27,269 | Milt Wilcox | Bruce Kison | Aurelio Lopez | John Montague | | 129 | 136 | -7 |
| 1980-05-10 | @ CAL | 27 | W 6-1 | 11-16 | 7 | 35,007 | Dan Schatzeder | Frank Tanana | Dan Schatzeder | Frank Tanana | | 135 | 137 | -2 |
| 1980-05-11 | @ CAL | 28 | W 4-0 | 12-16 | 6 | 31,089 | Dan Petry | Don Aase | Dan Petry | Don Aase | | 139 | 137 | 2 |
| 1980-05-13 | vs OAK | 29 | W 4-3 | 13-16 | 5 | 13,332 | Jack Morris | Matt Keough | Jack Morris | Matt Keough | Aurelio Lopez | 143 | 140 | 3 |
| 1980-05-14 | vs OAK | 30 | W 6-5 | 14-16 | 5 | 16,694 | Milt Wilcox | Rick Langford | Aurelio Lopez | Jeff Jones | | 149 | 145 | 4 |
| 1980-05-16 | vs BAL | 31 | L 1-2 | 14-17 | 5 | 34,243 | Dan Petry | Mike Flanagan | Mike Flanagan | Dan Petry | | 150 | 147 | 3 |
| 1980-05-18 | vs BAL | 32 | W 6-4 | 15-17 | 5 | 24,485 | Jack Morris | Scott McGregor | Aurelio Lopez | Tim Stoddard | | 156 | 151 | 5 |
| 1980-05-19 | vs NYA | 33 | L 0-1 | 15-18 | 5 | 27,715 | Milt Wilcox | Ron Guidry | Ron Guidry | Milt Wilcox | | 156 | 152 | 4 |
| 1980-05-20 | vs NYA | 34 | W 12-8 | 16-18 | 5 | 31,194 | Pat Underwood | Tommy John | John Hiller | Tommy John | Dave Rozema | 168 | 160 | 8 |
| 1980-05-21 | vs NYA | 35 | L 5-9 | 16-19 | 5 | 32,478 | Dan Schatzeder | Tom Underwood | Rudy May | Aurelio Lopez | | 173 | 169 | 4 |
| 1980-05-22 | @ BAL | 36 | L 1-5 | 16-20 | 6 | 15,835 | Dan Petry | Scott McGregor | Scott McGregor | Dan Petry | | 174 | 174 | 0 |
| 1980-05-23 | @ BAL | 37 | L 3-5 | 16-21 | 6 | 16,274 | Jack Morris | Steve Stone | Steve Stone | Jack Morris | Tippy Martinez | 177 | 179 | -2 |
| 1980-05-24 | @ BAL | 38 | L 1-9 | 16-22 | 7 | 29,384 | Milt Wilcox | Jim Palmer | Jim Palmer | Milt Wilcox | | 178 | 188 | -10 |
| 1980-05-25 | @ BAL | 39 | W 6-4 | 17-22 | 7 | 24,558 | Pat Underwood | Mike Flanagan | Aurelio Lopez | Tippy Martinez | | 184 | 192 | -8 |
| 1980-05-26 | @ NYA | 40 | L 5-13 | 17-23 | 7 | 28,170 | Dan Schatzeder | Tom Underwood | Tom Underwood | Dan Schatzeder | Rich Gossage | 189 | 205 | -16 |
| 1980-05-27 | @ NYA | 41 | L 6-9 | 17-24 | 7 | 20,150 | Dan Petry | Mike Griffin | Mike Griffin | Dan Petry | Ron Davis | 195 | 214 | -19 |
| 1980-05-28 | @ NYA | 42 | W 6-3 | 18-24 | 7 | 26,382 | Jack Morris | Ron Guidry | Jack Morris | Ron Guidry | Aurelio Lopez | 201 | 217 | -16 |
| 1980-05-30 | vs CAL | 43 | W 12-1 | 19-24 | 7 | 22,163 | Milt Wilcox | Frank Tanana | Milt Wilcox | Frank Tanana | | 213 | 218 | -5 |
| 1980-05-31 | vs CAL | 44 | L 1-6 | 19-25 | 7 | 23,350 | Pat Underwood | Bruce Kison | Bruce Kison | Pat Underwood | Dave LaRoche | 214 | 224 | -10 |
| 1980-06-02 | vs SEA | 45 | W 3-3 | 20-25 | 7 | 12,291 | Jack Morris | Rick Honeycutt | | | | 217 | 227 | -10 |
| 1980-06-03 | vs SEA | 46 | W 4-2 | 21-25 | 7 | 13,942 | Dan Petry | Dave Roberts | Aurelio Lopez | Byron McLaughlin | | 221 | 229 | -8 |
| 1980-06-04 | vs SEA | 47 | W 8-2 | 22-25 | 7 | 14,566 | Milt Wilcox | Floyd Bannister | Milt Wilcox | Floyd Bannister | | 229 | 231 | -2 |
| 1980-06-06 | @ MIL | 48 | L 4-8 | 22-26 | 7 | 35,192 | Pat Underwood | Mike Caldwell | Mike Caldwell | Pat Underwood | Jerry Augustine | 233 | 239 | -6 |
| 1980-06-07 | @ MIL | 49 | L 3-5 | 22-27 | 7 | 38,011 | Jack Morris | Rickey Keeton | Rickey Keeton | Jack Morris | | 236 | 244 | -8 |
| 1980-06-08 | @ MIL | 50 | W 9-5 | 23-27 | 7 | 40,892 | Dan Petry | Bill Travers | Dan Petry | Bill Travers | | 245 | 249 | -4 |
| 1980-06-10 | vs MIN | 51 | W 8-3 | 24-27 | 7 | 12,399 | Milt Wilcox | Geoff Zahn | Milt Wilcox | Geoff Zahn | | 253 | 252 | 1 |
| 1980-06-11 | vs MIN | 52 | L 5-9 | 24-28 | 7 | 16,017 | Dave Rozema | Darrell Jackson | Darrell Jackson | Dave Rozema | Jerry Koosman | 258 | 261 | -3 |
| 1980-06-12 | vs MIN | 53 | W 8-4 | 25-28 | 7 | 15,630 | Pat Underwood | Pete Redfern | Pat Underwood | Geoff Zahn | Aurelio Lopez | 266 | 265 | 1 |
| 1980-06-13 | vs CHA | 54 | W 8-4 | 26-28 | 6 | 33,767 | Jack Morris | Steve Trout | Jack Morris | Steve Trout | | 274 | 269 | 5 |
| 1980-06-14 | vs CHA | 55 | W 3-0 | 27-28 | 5 | 31,008 | Dan Petry | Britt Burns | Dan Petry | Britt Burns | | 277 | 269 | 8 |
| 1980-06-16 | vs MIL | 56 | W 6-5 | 28-29 | 6 | 0 | Milt Wilcox | Lary Sorensen | Milt Wilcox | Bill Castro | | 283 | 274 | 9 |
| 1980-06-16 | vs MIL | 57 | L 3-5 | 28-29 | 6 | 37,040 | Dave Rozema | Reggie Cleveland | Reggie Cleveland | Dave Rozema | John Flinn | 286 | 279 | 7 |
| 1980-06-17 | vs MIL | 58 | W 3-0 | 29-29 | 6 | 24,942 | Jack Morris | Mike Caldwell | Jack Morris | Mike Caldwell | | 289 | 279 | 10 |
| 1980-06-19 | @ MIN | 59 | L 1-5 | 29-30 | 7 | 14,704 | Dan Schatzeder | Darrell Jackson | Darrell Jackson | Dan Schatzeder | | 290 | 284 | 6 |
| 1980-06-20 | @ CHA | 60 | W 5-3 | 30-30 | 6 | 27,241 | Dan Petry | Britt Burns | Aurelio Lopez | Ed Farmer | | 295 | 287 | 8 |
| 1980-06-21 | @ CHA | 61 | W 4-1 | 31-30 | 6 | 23,990 | Milt Wilcox | Ross Baumgarten | Milt Wilcox | Ross Baumgarten | | 299 | 288 | 11 |
| 1980-06-22 | @ CHA | 62 | W 7-1 | 33-30 | 5 | 0 | Dave Rozema | Ken Kravec | Dave Rozema | Ken Kravec | | 306 | 289 | 17 |
| 1980-06-22 | @ CHA | 63 | W 6-4 | 33-30 | 5 | 27,100 | Jack Morris | Rich Wortham | Jack Morris | Rich Wortham | Aurelio Lopez | 312 | 293 | 19 |
| 1980-06-23 | @ CLE | 64 | W 5-4 | 34-30 | 4 | 19,564 | Pat Underwood | Bob Owchinko | Dan Schatzeder | Mike Stanton | | 317 | 297 | 20 |
| 1980-06-24 | @ CLE | 65 | W 9-4 | 35-30 | 3 | 11,692 | Dan Petry | Len Barker | Roger Weaver | Len Barker | Aurelio Lopez | 326 | 301 | 25 |
| 1980-06-25 | @ CLE | 66 | W 13-3 | 36-30 | 3 | 11,873 | Milt Wilcox | Dan Spillner | Milt Wilcox | Dan Spillner | | 339 | 304 | 35 |
| 1980-06-27 | @ TOR | 67 | W 7-2 | 37-30 | 3 | 18,494 | Jack Morris | Jesse Jefferson | Jack Morris | Jesse Jefferson | | 346 | 306 | 40 |
| 1980-06-28 | @ TOR | 68 | W 8-3 | 38-30 | 3 | 20,059 | Dave Rozema | Jack Kucek | Dave Rozema | Jack Kucek | | 354 | 309 | 45 |
| 1980-06-29 | @ TOR | 69 | L 0-2 | 38-31 | 3 | 22,026 | Dan Petry | Dave Stieb | Dave Stieb | Dan Petry | | 354 | 311 | 43 |
| 1980-06-30 | vs CLE | 70 | W 9-4 | 39-31 | 3 | 30,085 | Milt Wilcox | Dan Spillner | Dan Schatzeder | Dan Spillner | Aurelio Lopez | 363 | 315 | 48 |
| 1980-07-01 | vs CLE | 71 | L 7-8 | 39-32 | 3 | 27,830 | Bruce Robbins | John Denny | Bob Owchinko | Pat Underwood | Mike Stanton | 370 | 323 | 47 |
| 1980-07-02 | vs CLE | 72 | W 7-6 | 40-32 | 3 | 25,981 | Jack Morris | Rick Waits | Jack Morris | Rick Waits | Aurelio Lopez | 377 | 329 | 48 |
| 1980-07-03 | vs TOR | 73 | W 8-5 | 41-32 | 3 | 30,027 | Dave Rozema | Jack Kucek | Pat Underwood | Joey McLaughlin | | 385 | 334 | 51 |
| 1980-07-04 | vs TOR | 74 | W 4-3 | 42-32 | 2 | 29,370 | Dan Petry | Dave Stieb | Dan Petry | Dave Stieb | Aurelio Lopez | 389 | 337 | 52 |
| 1980-07-05 | vs TOR | 75 | L 3-5 | 42-33 | 3 | 32,925 | Milt Wilcox | Jim Clancy | Jim Clancy | Milt Wilcox | Jerry Garvin | 392 | 342 | 50 |
| 1980-07-06 | vs TOR | 76 | W 7-5 | 43-33 | 2 | 28,564 | Jack Morris | Joey McLaughlin | Jack Morris | Jerry Garvin | Aurelio Lopez | 399 | 347 | 52 |
| 1980-07-10 | @ KCA | 77 | L 2-3 | 43-34 | 2 | 23,684 | Milt Wilcox | Paul Splittorff | Paul Splittorff | Milt Wilcox | Dan Quisenberry | 401 | 350 | 51 |
| 1980-07-11 | @ KCA | 78 | L 3-7 | 43-35 | 3 | 31,017 | Jack Morris | Dennis Leonard | Dennis Leonard | Jack Morris | | 404 | 357 | 47 |
| 1980-07-12 | @ BOS | 79 | L 3-9 | 43-36 | 3 | 31,302 | Dan Petry | John Tudor | John Tudor | Dan Petry | | 407 | 366 | 41 |
| 1980-07-13 | @ BOS | 80 | L 4-8 | 43-37 | 3 | 31,228 | Dave Rozema | Bob Ojeda | Dick Drago | Dave Rozema | | 411 | 374 | 37 |
| 1980-07-14 | @ BOS | 81 | W 12-4 | 44-37 | 3 | 26,044 | Bruce Robbins | Mike Torrez | Bruce Robbins | Mike Torrez | Aurelio Lopez | 423 | 378 | 45 |
| 1980-07-16 | @ OAK | 82 | W 7-2 | 45-37 | 3 | 7,413 | Milt Wilcox | Brian Kingman | Roger Weaver | Brian Kingman | | 430 | 380 | 50 |
| 1980-07-17 | @ OAK | 83 | L 2-5 | 45-38 | 4 | 6,370 | Jack Morris | Matt Keough | Matt Keough | Jack Morris | | 432 | 385 | 47 |
| 1980-07-18 | @ SEA | 84 | W 5-3 | 46-38 | 4 | 7,479 | Dan Petry | Jim Beattie | Aurelio Lopez | Jim Beattie | | 437 | 388 | 49 |
| 1980-07-19 | @ SEA | 85 | W 5-3 | 47-38 | 2 | 16,525 | Bruce Robbins | Rick Honeycutt | Dave Rozema | Rick Honeycutt | | 442 | 391 | 51 |
| 1980-07-20 | @ SEA | 86 | W 5-2 | 48-38 | 2 | 7,583 | Dan Schatzeder | Mike Parrott | Dan Schatzeder | Mike Parrott | | 447 | 393 | 54 |
| 1980-07-21 | @ CAL | 87 | W 14-3 | 49-38 | 2 | 24,594 | Milt Wilcox | Don Aase | Milt Wilcox | Don Aase | Pat Underwood | 461 | 396 | 65 |
| 1980-07-22 | @ CAL | 88 | L 4-6 | 49-39 | 3 | 24,137 | Jack Morris | Chris Knapp | Andy Hassler | Dave Rozema | Mark Clear | 465 | 402 | 63 |
| 1980-07-23 | @ CAL | 89 | W 7-6 | 50-39 | 2 | 26,648 | Dan Petry | Dave LaRoche | Aurelio Lopez | Mark Clear | | 472 | 408 | 64 |
| 1980-07-25 | vs OAK | 90 | L 3-5 | 50-40 | 3 | 41,229 | Bruce Robbins | Rick Langford | Rick Langford | Bruce Robbins | | 475 | 413 | 62 |
| 1980-07-26 | vs OAK | 91 | W 7-0 | 51-40 | 2 | 39,758 | Dan Schatzeder | Brian Kingman | Dan Schatzeder | Brian Kingman | | 482 | 413 | 69 |
| 1980-07-27 | vs OAK | 92 | W 4-2 | 52-41 | 2 | 0 | Milt Wilcox | Craig Minetto | Milt Wilcox | Craig Minetto | | 486 | 415 | 71 |
| 1980-07-27 | vs OAK | 93 | L 0-4 | 52-41 | 2 | 44,093 | Jack Morris | Matt Keough | Matt Keough | Jack Morris | Bob Lacey | 486 | 419 | 67 |
| 1980-07-28 | vs CAL | 94 | L 2-3 | 52-42 | 2 | 25,804 | Dan Petry | Dave LaRoche | John Montague | Dan Petry | Andy Hassler | 488 | 422 | 66 |
| 1980-07-29 | vs CAL | 95 | L 0-7 | 52-43 | 4 | 23,020 | Bruce Robbins | Alfredo Martinez | Alfredo Martinez | Bruce Robbins | | 488 | 429 | 59 |
| 1980-07-30 | vs CAL | 96 | L 5-6 | 52-44 | 4 | 21,907 | Dan Schatzeder | Frank Tanana | Mark Clear | Dan Schatzeder | Andy Hassler | 493 | 435 | 58 |
| 1980-07-31 | vs CAL | 97 | W 15-6 | 53-44 | 3 | 19,850 | Milt Wilcox | Don Aase | Milt Wilcox | Don Aase | Dave Rozema | 508 | 441 | 67 |
| 1980-08-01 | vs SEA | 98 | W 1-0 | 55-44 | 3 | 0 | Jack Morris | Floyd Bannister | Jack Morris | Floyd Bannister | | 509 | 441 | 68 |
| 1980-08-01 | vs SEA | 99 | W 5-2 | 55-44 | 3 | 32,910 | Dan Petry | Rob Dressler | Dan Petry | Rob Dressler | Aurelio Lopez | 514 | 443 | 71 |
| 1980-08-02 | vs SEA | 100 | W 9-3 | 56-44 | 3 | 23,278 | Bruce Robbins | Jim Beattie | Bruce Robbins | Jim Beattie | Aurelio Lopez | 523 | 446 | 77 |
| 1980-08-03 | vs SEA | 101 | W 4-3 | 57-44 | 3 | 25,454 | Roger Weaver | Rick Honeycutt | Dave Rozema | Rick Honeycutt | Aurelio Lopez | 527 | 449 | 78 |
| 1980-08-04 | vs KCA | 102 | L 5-6 | 57-45 | 3 | 37,016 | Dan Schatzeder | Steve Busby | Dan Quisenberry | Dan Schatzeder | | 532 | 455 | 77 |
| 1980-08-05 | vs KCA | 103 | L 3-6 | 57-46 | 3 | 27,469 | Milt Wilcox | Dennis Leonard | Dennis Leonard | Milt Wilcox | Dan Quisenberry | 535 | 461 | 74 |
| 1980-08-06 | vs KCA | 104 | L 4-5 | 57-47 | 3 | 29,115 | Jack Morris | Larry Gura | Larry Gura | Jack Morris | Dan Quisenberry | 539 | 466 | 73 |
| 1980-08-08 | @ TEX | 105 | W 8-0 | 58-47 | 3 | 14,138 | Dan Petry | Ed Figueroa | Dan Petry | Ed Figueroa | | 547 | 466 | 81 |
| 1980-08-09 | @ TEX | 106 | L 3-4 | 58-48 | 3 | 19,021 | Dan Schatzeder | Jon Matlack | Danny Darwin | Aurelio Lopez | | 550 | 470 | 80 |
| 1980-08-10 | @ TEX | 107 | L 2-4 | 58-49 | 3 | 11,752 | Roger Weaver | Gaylord Perry | Gaylord Perry | Roger Weaver | Danny Darwin | 552 | 474 | 78 |
| 1980-08-11 | vs BOS | 108 | W 8-7 | 59-49 | 3 | 28,222 | Jack Morris | Bob Ojeda | Aurelio Lopez | Tom Burgmeier | | 560 | 481 | 79 |
| 1980-08-12 | vs BOS | 109 | L 4-5 | 59-50 | 3 | 48,361 | Mark Fidrych | Mike Torrez | Bill Campbell | Mark Fidrych | Bob Stanley | 564 | 486 | 78 |
| 1980-08-13 | vs BOS | 110 | W 2-1 | 60-50 | 3 | 24,565 | Dan Petry | John Tudor | Dan Petry | John Tudor | Aurelio Lopez | 566 | 487 | 79 |
| 1980-08-14 | vs BOS | 111 | L 1-3 | 60-51 | 3 | 25,579 | Dan Schatzeder | Steve Renko | Steve Renko | Dan Schatzeder | Bob Stanley | 567 | 490 | 77 |
| 1980-08-15 | vs TEX | 112 | L 2-6 | 60-52 | 3 | 30,247 | Pat Underwood | Jon Matlack | Jon Matlack | Pat Underwood | | 569 | 496 | 73 |
| 1980-08-16 | vs TEX | 113 | L 5-12 | 60-53 | 4 | 33,868 | Jack Morris | Ken Clay | Ken Clay | Jack Morris | Danny Darwin | 574 | 508 | 66 |
| 1980-08-17 | vs TEX | 114 | L 3-9 | 60-55 | 5 | 0 | Mark Fidrych | Fergie Jenkins | Fergie Jenkins | Mark Fidrych | | 577 | 517 | 60 |
| 1980-08-17 | vs TEX | 115 | L 6-12 | 60-55 | 5 | 42,117 | Milt Wilcox | Doc Medich | Doc Medich | Milt Wilcox | | 583 | 529 | 54 |
| 1980-08-18 | @ MIL | 116 | L 5-12 | 60-56 | 5 | 22,237 | Dan Petry | Bill Travers | Bill Travers | Dan Petry | | 588 | 541 | 47 |
| 1980-08-19 | @ MIL | 117 | W 6-2 | 61-56 | 5 | 40,318 | Dan Schatzeder | Moose Haas | Dan Schatzeder | Moose Haas | | 594 | 543 | 51 |
| 1980-08-20 | @ MIL | 118 | W 8-6 | 62-56 | 5 | 20,520 | Jerry Ujdur | Mike Caldwell | Jerry Ujdur | Mike Caldwell | Aurelio Lopez | 602 | 549 | 53 |
| 1980-08-21 | @ MIN | 119 | L 3-5 | 63-57 | 5 | 0 | Milt Wilcox | Albert Williams | Albert Williams | Milt Wilcox | Doug Corbett | 605 | 554 | 51 |
| 1980-08-21 | @ MIN | 120 | W 4-2 | 63-57 | 5 | 8,687 | Jack Morris | Roger Erickson | Jack Morris | Roger Erickson | | 609 | 556 | 53 |
| 1980-08-22 | @ MIN | 121 | L 5-6 | 63-58 | 6 | 12,473 | Mark Fidrych | Jerry Koosman | Fernando Arroyo | Dave Rozema | | 614 | 562 | 52 |
| 1980-08-23 | @ MIN | 122 | W 4-3 | 64-58 | 5 | 7,062 | Dan Petry | Darrell Jackson | Bruce Robbins | Darrell Jackson | Dave Rozema | 618 | 565 | 53 |
| 1980-08-24 | @ MIN | 123 | W 3-2 | 65-58 | 5 | 11,859 | Dan Schatzeder | Geoff Zahn | Dan Schatzeder | Geoff Zahn | | 621 | 567 | 54 |
| 1980-08-26 | @ CHA | 124 | W 5-4 | 66-58 | 4 | 10,061 | Jerry Ujdur | LaMarr Hoyt | Aurelio Lopez | Rich Wortham | Pat Underwood | 626 | 571 | 55 |
| 1980-08-27 | @ CHA | 125 | L 2-3 | 66-59 | 4 | 12,582 | Jack Morris | Britt Burns | Mike Proly | Dave Rozema | | 628 | 574 | 54 |
| 1980-08-28 | vs MIL | 126 | W 11-7 | 67-59 | 4 | 26,318 | Mark Fidrych | Lary Sorensen | Bruce Robbins | Bob McClure | Pat Underwood | 639 | 581 | 58 |
| 1980-08-29 | vs MIL | 127 | W 8-2 | 68-59 | 4 | 24,400 | Milt Wilcox | Bill Travers | Milt Wilcox | Bill Travers | | 647 | 583 | 64 |
| 1980-08-30 | vs MIL | 128 | L 4-6 | 68-60 | 4 | 26,051 | Aurelio Lopez | Moose Haas | Moose Haas | Aurelio Lopez | | 651 | 589 | 62 |
| 1980-08-31 | vs MIL | 129 | L 6-11 | 68-61 | 4 | 21,684 | Dan Schatzeder | Mike Caldwell | Reggie Cleveland | Dan Schatzeder | | 657 | 600 | 57 |
| 1980-09-01 | vs CHA | 130 | L 3-11 | 68-62 | 5 | 11,412 | Jack Morris | Britt Burns | Britt Burns | Jack Morris | | 660 | 611 | 49 |
| 1980-09-02 | vs CHA | 131 | W 11-2 | 70-62 | 4 | 0 | Mark Fidrych | Mike Proly | Mark Fidrych | Mike Proly | | 671 | 613 | 58 |
| 1980-09-02 | vs CHA | 132 | W 6-1 | 70-62 | 4 | 13,651 | Milt Wilcox | Richard Dotson | Milt Wilcox | Richard Dotson | | 677 | 614 | 63 |
| 1980-09-03 | vs CHA | 133 | W 5-4 | 71-62 | 4 | 10,395 | Dave Rozema | Guy Hoffman | Aurelio Lopez | Rich Wortham | | 682 | 618 | 64 |
| 1980-09-05 | vs MIN | 134 | W 1-0 | 72-62 | 4 | 16,980 | Dan Schatzeder | Roger Erickson | Dan Schatzeder | Roger Erickson | | 683 | 618 | 65 |
| 1980-09-06 | vs MIN | 135 | L 0-4 | 72-63 | 4 | 18,249 | Jack Morris | Jerry Koosman | Jerry Koosman | Jack Morris | Doug Corbett | 683 | 622 | 61 |
| 1980-09-07 | vs MIN | 136 | L 1-3 | 72-64 | 4 | 20,009 | Mark Fidrych | Darrell Jackson | Darrell Jackson | Mark Fidrych | Doug Corbett | 684 | 625 | 59 |
| 1980-09-08 | vs BAL | 137 | L 2-9 | 72-66 | 5 | 0 | Milt Wilcox | Dennis Martinez | Dennis Martinez | Milt Wilcox | Sammy Stewart | 686 | 634 | 52 |
| 1980-09-08 | vs BAL | 138 | L 6-8 | 72-66 | 5 | 19,445 | Dan Petry | Mike Flanagan | Mike Flanagan | Dan Petry | Tim Stoddard | 692 | 642 | 50 |
| 1980-09-09 | vs BAL | 139 | L 0-2 | 72-67 | 5 | 13,450 | Dan Schatzeder | Scott McGregor | Scott McGregor | Dan Schatzeder | | 692 | 644 | 48 |
| 1980-09-10 | vs BAL | 140 | L 4-8 | 72-68 | 6 | 14,155 | Jack Morris | Jim Palmer | Tippy Martinez | Jack Morris | Tim Stoddard | 696 | 652 | 44 |
| 1980-09-12 | @ CLE | 141 | W 6-3 | 73-68 | 5 | 9,961 | Mark Fidrych | Len Barker | Aurelio Lopez | Len Barker | | 702 | 655 | 47 |
| 1980-09-13 | @ CLE | 142 | W 7-4 | 74-68 | 5 | 6,380 | Milt Wilcox | Wayne Garland | Pat Underwood | Mike Stanton | Dave Rozema | 709 | 659 | 50 |
| 1980-09-14 | @ CLE | 143 | L 4-5 | 74-70 | 6 | 0 | Dan Schatzeder | Dan Spillner | Victor Cruz | Aurelio Lopez | | 713 | 664 | 49 |
| 1980-09-14 | @ CLE | 144 | L 0-3 | 74-70 | 6 | 10,189 | Dan Petry | Bob Owchinko | Bob Owchinko | Dan Petry | | 713 | 667 | 46 |
| 1980-09-16 | @ BAL | 145 | W 8-3 | 75-70 | 5 | 10,992 | Jack Morris | Steve Stone | Jack Morris | Steve Stone | | 721 | 670 | 51 |
| 1980-09-17 | @ BAL | 146 | L 3-9 | 75-71 | 6 | 9,915 | Roger Weaver | Mike Flanagan | Sammy Stewart | Roger Weaver | | 724 | 679 | 45 |
| 1980-09-18 | @ BAL | 147 | L 3-7 | 75-72 | 6 | 10,272 | Milt Wilcox | Scott McGregor | Scott McGregor | Milt Wilcox | Tim Stoddard | 727 | 686 | 41 |
| 1980-09-19 | vs CLE | 148 | W 4-3 | 76-72 | 5 | 10,822 | Dan Schatzeder | Bob Owchinko | Dan Schatzeder | Bob Owchinko | Aurelio Lopez | 731 | 689 | 42 |
| 1980-09-20 | vs CLE | 149 | W 13-3 | 77-72 | 5 | 10,985 | Dan Petry | Rick Waits | Dan Petry | Rick Waits | | 744 | 692 | 52 |
| 1980-09-21 | vs CLE | 150 | W 13-1 | 78-72 | 5 | 10,682 | Jack Morris | Dan Spillner | Jack Morris | Dan Spillner | Pat Underwood | 757 | 693 | 64 |
| 1980-09-22 | vs TOR | 151 | L 5-6 | 78-73 | 5 | 6,210 | Roger Weaver | Joey McLaughlin | Jerry Garvin | Roger Weaver | Mike Willis | 762 | 699 | 63 |
| 1980-09-23 | vs TOR | 152 | L 7-9 | 78-74 | 5 | 6,363 | Milt Wilcox | Luis Leal | Mike Willis | Dave Rozema | Jack Kucek | 769 | 708 | 61 |
| 1980-09-24 | vs TOR | 153 | W 9-8 | 79-74 | 5 | 7,129 | Mark Fidrych | Jackson Todd | Dan Petry | Jack Kucek | | 778 | 716 | 62 |
| 1980-09-26 | vs NYA | 154 | L 5-7 | 79-75 | 5 | 30,864 | Dan Schatzeder | Ron Guidry | Ron Guidry | Dan Schatzeder | Ron Davis | 783 | 723 | 60 |
| 1980-09-27 | vs NYA | 155 | W 5-1 | 80-75 | 5 | 27,318 | Jack Morris | Tommy John | Jack Morris | Tommy John | Aurelio Lopez | 788 | 724 | 64 |
| 1980-09-28 | vs NYA | 156 | W 6-5 | 81-75 | 5 | 25,142 | Dan Petry | Tom Underwood | Aurelio Lopez | Mike Griffin | | 794 | 729 | 65 |
| 1980-09-29 | @ TOR | 157 | W 8-2 | 82-75 | 5 | 12,051 | Roger Weaver | Paul Mirabella | Roger Weaver | Paul Mirabella | Aurelio Lopez | 802 | 731 | 71 |
| 1980-09-30 | @ TOR | 158 | W 5-3 | 83-75 | 5 | 12,119 | Dan Schatzeder | Jackson Todd | Dan Schatzeder | Jackson Todd | | 807 | 734 | 73 |
| 1980-10-01 | @ TOR | 159 | W 11-7 | 84-75 | 4 | 12,426 | Mark Fidrych | Dave Stieb | Mark Fidrych | Dave Stieb | Pat Underwood | 818 | 741 | 77 |
| 1980-10-02 | @ NYA | 160 | L 2-3 | 84-76 | 5 | 24,316 | Jack Morris | Ron Guidry | Ron Guidry | Jack Morris | Rich Gossage | 820 | 744 | 76 |
| 1980-10-04 | @ NYA | 161 | L 2-5 | 85-77 | 4 | 0 | Roger Weaver | Rudy May | Rudy May | Roger Weaver | Rich Gossage | 822 | 749 | 73 |
| 1980-10-04 | @ NYA | 162 | W 7-6 | 85-77 | 4 | 55,410 | Dave Tobik | Mike Griffin | Dave Tobik | Mike Griffin | | 829 | 755 | 74 |
| 1980-10-05 | @ NYA | 163 | L 1-2 | 85-78 | 4 | 35,879 | Dan Schatzeder | Tim Lollar | Tim Lollar | Dan Schatzeder | Doug Bird | 830 | 757 | 73 |