| 1980-04-10 | @ MIL | 1 | L 5-9 | 0-1 | 4 | 53,313 | Dennis Eckersley | Jim Slaton | Reggie Cleveland | Dick Drago | | 5 | 9 | -4 |
| 1980-04-12 | @ MIL | 2 | L 1-18 | 0-2 | 6 | 16,962 | Mike Torrez | Lary Sorensen | Lary Sorensen | Mike Torrez | | 6 | 27 | -21 |
| 1980-04-13 | @ MIL | 3 | W 3-1 | 1-2 | 3 | 17,574 | Bob Stanley | Moose Haas | Bob Stanley | Moose Haas | | 9 | 28 | -19 |
| 1980-04-14 | vs DET | 4 | W 3-1 | 2-2 | 2 | 33,512 | Dennis Eckersley | Jack Morris | Dennis Eckersley | Jack Morris | Tom Burgmeier | 12 | 29 | -17 |
| 1980-04-16 | vs DET | 5 | W 10-9 | 3-2 | 1 | 9,238 | Bruce Hurst | Dan Schatzeder | Steve Renko | Dan Schatzeder | Tom Burgmeier | 22 | 38 | -16 |
| 1980-04-17 | vs DET | 6 | W 5-4 | 4-2 | 1 | 8,626 | Mike Torrez | Milt Wilcox | Dick Drago | Aurelio Lopez | | 27 | 42 | -15 |
| 1980-04-18 | vs TEX | 7 | L 5-6 | 4-3 | 2 | 10,580 | Bob Stanley | Steve Comer | Danny Darwin | Skip Lockwood | Jim Kern | 32 | 48 | -16 |
| 1980-04-19 | vs TEX | 8 | L 0-8 | 4-4 | 3 | 22,715 | Dennis Eckersley | Gaylord Perry | Gaylord Perry | Dennis Eckersley | | 32 | 56 | -24 |
| 1980-04-20 | vs TEX | 9 | W 6-5 | 5-4 | 1 | 23,696 | Chuck Rainey | Doc Medich | Tom Burgmeier | Jim Kern | | 38 | 61 | -23 |
| 1980-04-21 | vs CHA | 10 | W 9-8 | 6-4 | 1 | 27,990 | Bruce Hurst | Ken Kravec | Skip Lockwood | Randy Scarbery | Dick Drago | 47 | 69 | -22 |
| 1980-04-22 | vs CHA | 11 | L 0-2 | 6-5 | 2 | 13,230 | Mike Torrez | Britt Burns | Britt Burns | Mike Torrez | Mike Proly | 47 | 71 | -24 |
| 1980-04-24 | vs CHA | 12 | L 3-9 | 6-6 | 3 | 12,385 | Bob Stanley | Richard Dotson | Richard Dotson | Bob Stanley | Ed Farmer | 50 | 80 | -30 |
| 1980-04-25 | @ DET | 13 | L 3-11 | 6-7 | 4 | 11,581 | Dennis Eckersley | Dan Schatzeder | Dan Schatzeder | Dennis Eckersley | | 53 | 91 | -38 |
| 1980-04-26 | @ DET | 14 | W 12-7 | 7-7 | 2 | 20,261 | Bruce Hurst | Milt Wilcox | Bruce Hurst | Milt Wilcox | Tom Burgmeier | 65 | 98 | -33 |
| 1980-04-27 | @ DET | 15 | L 5-8 | 7-8 | 3 | 16,882 | Mike Torrez | Dave Rozema | Dave Rozema | Mike Torrez | Aurelio Lopez | 70 | 106 | -36 |
| 1980-04-29 | @ CHA | 16 | W 11-1 | 8-8 | 3 | 9,253 | Bob Stanley | Ross Baumgarten | Bob Stanley | Ross Baumgarten | | 81 | 107 | -26 |
| 1980-04-30 | @ CHA | 17 | L 1-2 | 8-9 | 3 | 10,626 | Dennis Eckersley | Richard Dotson | Richard Dotson | Dennis Eckersley | Ed Farmer | 82 | 109 | -27 |
| 1980-05-01 | @ CHA | 18 | W 4-3 | 9-9 | 2 | 8,155 | Bruce Hurst | Steve Trout | Bruce Hurst | Steve Trout | Tom Burgmeier | 86 | 112 | -26 |
| 1980-05-02 | @ KCA | 19 | W 6-5 | 10-9 | 1 | 25,965 | Mike Torrez | Rich Gale | Skip Lockwood | Dan Quisenberry | | 92 | 117 | -25 |
| 1980-05-03 | @ KCA | 20 | W 7-0 | 11-9 | 1 | 28,760 | Chuck Rainey | Paul Splittorff | Chuck Rainey | Paul Splittorff | | 99 | 117 | -18 |
| 1980-05-04 | @ KCA | 21 | L 3-5 | 11-10 | 4 | 24,209 | Bob Stanley | Dennis Leonard | Dennis Leonard | Bob Stanley | Dan Quisenberry | 102 | 122 | -20 |
| 1980-05-05 | @ TEX | 22 | L 3-11 | 11-11 | 4 | 12,702 | Dennis Eckersley | Gaylord Perry | Gaylord Perry | Dennis Eckersley | | 105 | 133 | -28 |
| 1980-05-06 | @ TEX | 23 | L 2-7 | 11-12 | 4 | 11,349 | Bruce Hurst | Doc Medich | Doc Medich | Bruce Hurst | | 107 | 140 | -33 |
| 1980-05-07 | @ TEX | 24 | W 7-4 | 12-12 | 3 | 13,866 | Mike Torrez | Jon Matlack | Dick Drago | Adrian Devine | | 114 | 144 | -30 |
| 1980-05-09 | vs KCA | 25 | L 5-6 | 12-13 | 3 | 28,597 | Bob Stanley | Dennis Leonard | Dennis Leonard | Bob Stanley | Dan Quisenberry | 119 | 150 | -31 |
| 1980-05-10 | vs KCA | 26 | L 8-13 | 12-14 | 4 | 30,519 | Dennis Eckersley | Renie Martin | Renie Martin | Dennis Eckersley | Marty Pattin | 127 | 163 | -36 |
| 1980-05-11 | vs KCA | 27 | W 5-2 | 13-14 | 4 | 24,685 | Chuck Rainey | Rich Gale | Chuck Rainey | Rich Gale | | 132 | 165 | -33 |
| 1980-05-12 | vs MIN | 28 | L 3-4 | 13-15 | 4 | 18,486 | Mike Torrez | Pete Redfern | Pete Redfern | Mike Torrez | Doug Corbett | 135 | 169 | -34 |
| 1980-05-13 | vs MIN | 29 | W 10-5 | 14-15 | 4 | 19,032 | Bruce Hurst | Albert Williams | Steve Renko | John Verhoeven | Tom Burgmeier | 145 | 174 | -29 |
| 1980-05-14 | vs MIN | 30 | W 7-6 | 15-15 | 4 | 24,590 | Bob Stanley | Jerry Koosman | Tom Burgmeier | Doug Corbett | | 152 | 180 | -28 |
| 1980-05-15 | @ CLE | 31 | W 6-2 | 16-15 | 3 | 6,700 | Jack Billingham | Rick Waits | Jack Billingham | Rick Waits | Dick Drago | 158 | 182 | -24 |
| 1980-05-16 | @ CLE | 32 | W 2-1 | 17-15 | 3 | 10,157 | Chuck Rainey | John Denny | Chuck Rainey | John Denny | Tom Burgmeier | 160 | 183 | -23 |
| 1980-05-17 | @ CLE | 33 | L 3-4 | 17-16 | 3 | 20,245 | Mike Torrez | Len Barker | Mike Stanton | Keith MacWhorter | | 163 | 187 | -24 |
| 1980-05-18 | @ CLE | 34 | L 1-3 | 17-17 | 3 | 28,724 | Bob Stanley | Dan Spillner | Dan Spillner | Bob Stanley | Sid Monge | 164 | 190 | -26 |
| 1980-05-19 | @ TOR | 35 | L 2-7 | 17-18 | 3 | 32,731 | Jack Billingham | Jim Clancy | Jim Clancy | Jack Billingham | | 166 | 197 | -31 |
| 1980-05-20 | @ TOR | 36 | W 4-3 | 18-18 | 3 | 18,167 | Chuck Rainey | Dave Lemanczyk | Chuck Rainey | Dave Lemanczyk | Tom Burgmeier | 170 | 200 | -30 |
| 1980-05-21 | @ TOR | 37 | W 11-2 | 19-18 | 3 | 19,556 | Mike Torrez | Jesse Jefferson | Mike Torrez | Jesse Jefferson | | 181 | 202 | -21 |
| 1980-05-23 | vs CLE | 38 | W 4-1 | 20-18 | 3 | 21,857 | Bob Stanley | Dan Spillner | Bob Stanley | Dan Spillner | Tom Burgmeier | 185 | 203 | -18 |
| 1980-05-24 | vs CLE | 39 | L 2-7 | 20-19 | 3 | 22,719 | Jack Billingham | Rick Waits | Rick Waits | Jack Billingham | | 187 | 210 | -23 |
| 1980-05-25 | vs CLE | 40 | L 2-3 | 20-20 | 4 | 24,391 | Chuck Rainey | John Denny | John Denny | Chuck Rainey | | 189 | 213 | -24 |
| 1980-05-26 | vs TOR | 41 | L 1-3 | 20-21 | 4 | 18,853 | Mike Torrez | Jesse Jefferson | Jerry Garvin | Dick Drago | | 190 | 216 | -26 |
| 1980-05-27 | vs TOR | 42 | W 5-4 | 21-21 | 4 | 16,679 | Steve Renko | Paul Mirabella | Steve Renko | Tom Buskey | | 195 | 220 | -25 |
| 1980-05-28 | vs TOR | 43 | L 1-4 | 21-22 | 4 | 18,215 | Bob Stanley | Dave Stieb | Dave Stieb | Bob Stanley | Joey McLaughlin | 196 | 224 | -28 |
| 1980-05-30 | vs MIL | 44 | W 5-3 | 22-22 | 4 | 28,238 | Chuck Rainey | Lary Sorensen | Chuck Rainey | Lary Sorensen | Tom Burgmeier | 201 | 227 | -26 |
| 1980-05-31 | vs MIL | 45 | L 8-19 | 22-23 | 4 | 30,381 | Mike Torrez | Mike Caldwell | Reggie Cleveland | Mike Torrez | | 209 | 246 | -37 |
| 1980-06-01 | vs MIL | 46 | L 5-8 | 22-24 | 5 | 31,157 | Steve Renko | Rickey Keeton | John Flinn | Tom Burgmeier | Bill Castro | 214 | 254 | -40 |
| 1980-06-02 | @ MIN | 47 | W 6-2 | 23-24 | 4 | 6,322 | Bob Stanley | Pete Redfern | Bob Stanley | Pete Redfern | | 220 | 256 | -36 |
| 1980-06-03 | @ MIN | 48 | L 4-9 | 23-25 | 6 | 8,346 | Jack Billingham | Jerry Koosman | Jerry Koosman | Jack Billingham | | 224 | 265 | -41 |
| 1980-06-06 | @ OAK | 49 | W 14-8 | 24-25 | 4 | 15,947 | Chuck Rainey | Mike Norris | Chuck Rainey | Mike Norris | | 238 | 273 | -35 |
| 1980-06-07 | @ OAK | 50 | L 1-4 | 24-26 | 6 | 13,005 | Mike Torrez | Matt Keough | Matt Keough | Mike Torrez | | 239 | 277 | -38 |
| 1980-06-08 | @ OAK | 51 | W 6-1 | 25-26 | 5 | 18,738 | Dennis Eckersley | Brian Kingman | Tom Burgmeier | Dave Hamilton | | 245 | 278 | -33 |
| 1980-06-09 | @ SEA | 52 | L 7-8 | 25-27 | 6 | 10,132 | Bob Stanley | Mike Parrott | Dave Heaverlo | Dick Drago | | 252 | 286 | -34 |
| 1980-06-10 | @ SEA | 53 | W 5-4 | 26-27 | 5 | 10,223 | Steve Renko | Floyd Bannister | Skip Lockwood | Rob Dressler | | 257 | 290 | -33 |
| 1980-06-11 | @ SEA | 54 | W 7-5 | 27-27 | 3 | 10,086 | Chuck Rainey | Jim Beattie | Chuck Rainey | Jim Beattie | Tom Burgmeier | 264 | 295 | -31 |
| 1980-06-12 | @ CAL | 55 | W 13-2 | 28-27 | 3 | 27,960 | Mike Torrez | Dave Frost | Mike Torrez | Dave Frost | | 277 | 297 | -20 |
| 1980-06-13 | @ CAL | 56 | W 3-0 | 29-27 | 3 | 32,161 | Dennis Eckersley | Don Aase | Dennis Eckersley | Don Aase | Dick Drago | 280 | 297 | -17 |
| 1980-06-14 | @ CAL | 57 | W 7-3 | 30-27 | 3 | 32,133 | Bob Stanley | Alfredo Martinez | Bob Stanley | Alfredo Martinez | Tom Burgmeier | 287 | 300 | -13 |
| 1980-06-15 | @ CAL | 58 | W 6-5 | 31-27 | 3 | 40,261 | Steve Renko | Frank Tanana | Steve Renko | Frank Tanana | Skip Lockwood | 293 | 305 | -12 |
| 1980-06-16 | vs OAK | 59 | L 8-11 | 31-28 | 4 | 25,026 | Chuck Rainey | Mike Norris | Mike Norris | Chuck Rainey | | 301 | 316 | -15 |
| 1980-06-17 | vs OAK | 60 | W 6-2 | 32-28 | 3 | 24,722 | Mike Torrez | Matt Keough | Mike Torrez | Matt Keough | | 307 | 318 | -11 |
| 1980-06-18 | vs SEA | 61 | W 6-2 | 33-28 | 2 | 22,230 | Dennis Eckersley | Glenn Abbott | Dennis Eckersley | Glenn Abbott | | 313 | 320 | -7 |
| 1980-06-19 | vs SEA | 62 | W 2-0 | 34-28 | 2 | 23,032 | Bob Stanley | Mike Parrott | Bob Stanley | Mike Parrott | | 315 | 320 | -5 |
| 1980-06-20 | vs CAL | 63 | L 2-20 | 34-29 | 3 | 28,780 | Steve Renko | Frank Tanana | Frank Tanana | Steve Renko | | 317 | 340 | -23 |
| 1980-06-21 | vs CAL | 64 | L 2-4 | 34-30 | 3 | 33,442 | Chuck Rainey | Chris Knapp | Chris Knapp | Chuck Rainey | Andy Hassler | 319 | 344 | -25 |
| 1980-06-22 | vs CAL | 65 | W 6-3 | 35-30 | 3 | 30,938 | Mike Torrez | Jim Barr | Mike Torrez | Jim Barr | Tom Burgmeier | 325 | 347 | -22 |
| 1980-06-23 | @ NYA | 66 | W 7-2 | 36-30 | 3 | 50,139 | Dennis Eckersley | Ron Guidry | Dennis Eckersley | Ron Guidry | | 332 | 349 | -17 |
| 1980-06-24 | @ NYA | 67 | L 5-10 | 36-31 | 4 | 40,161 | Bob Stanley | Ed Figueroa | Rudy May | John Tudor | Rich Gossage | 337 | 359 | -22 |
| 1980-06-25 | @ NYA | 68 | W 4-3 | 37-31 | 4 | 46,500 | Steve Renko | Tommy John | Tom Burgmeier | Tommy John | | 341 | 362 | -21 |
| 1980-06-27 | vs BAL | 69 | W 3-2 | 38-31 | 4 | 31,607 | Chuck Rainey | Mike Flanagan | Chuck Rainey | Mike Flanagan | Tom Burgmeier | 344 | 364 | -20 |
| 1980-06-28 | vs BAL | 70 | L 4-8 | 38-32 | 4 | 30,914 | Mike Torrez | Scott McGregor | Scott McGregor | Mike Torrez | | 348 | 372 | -24 |
| 1980-06-30 | vs NYA | 71 | L 3-6 | 38-33 | 5 | 33,858 | Bob Stanley | Tommy John | Tommy John | Bob Stanley | Rich Gossage | 351 | 378 | -27 |
| 1980-07-01 | vs NYA | 72 | L 2-3 | 38-34 | 5 | 35,026 | Dennis Eckersley | Ed Figueroa | Ed Figueroa | Dennis Eckersley | Ron Davis | 353 | 381 | -28 |
| 1980-07-02 | vs NYA | 73 | L 0-6 | 38-35 | 5 | 33,971 | Steve Renko | Rudy May | Rudy May | Steve Renko | | 353 | 387 | -34 |
| 1980-07-03 | @ BAL | 74 | W 5-2 | 39-35 | 5 | 29,502 | Chuck Rainey | Scott McGregor | Win Remmerswaal | Scott McGregor | Tom Burgmeier | 358 | 389 | -31 |
| 1980-07-04 | @ BAL | 75 | L 3-10 | 39-36 | 5 | 28,668 | Mike Torrez | Steve Stone | Steve Stone | Mike Torrez | Tim Stoddard | 361 | 399 | -38 |
| 1980-07-05 | @ BAL | 76 | W 1-0 | 40-36 | 5 | 28,251 | John Tudor | Jim Palmer | John Tudor | Jim Palmer | Tom Burgmeier | 362 | 399 | -37 |
| 1980-07-06 | @ BAL | 77 | W 6-4 | 41-36 | 5 | 31,085 | Dennis Eckersley | Mike Flanagan | Dennis Eckersley | Mike Flanagan | Bob Stanley | 368 | 403 | -35 |
| 1980-07-10 | @ MIL | 78 | L 1-2 | 42-37 | 5 | 0 | Mike Torrez | Reggie Cleveland | Reggie Cleveland | Mike Torrez | | 369 | 405 | -36 |
| 1980-07-10 | @ MIL | 79 | W 7-0 | 42-37 | 5 | 40,942 | Steve Renko | Lary Sorensen | Steve Renko | Lary Sorensen | | 376 | 405 | -29 |
| 1980-07-11 | @ MIL | 80 | L 6-7 | 42-38 | 5 | 41,993 | Dennis Eckersley | Mike Caldwell | Mike Caldwell | Dennis Eckersley | Bill Castro | 382 | 412 | -30 |
| 1980-07-12 | vs DET | 81 | W 9-3 | 43-38 | 5 | 31,302 | John Tudor | Dan Petry | John Tudor | Dan Petry | | 391 | 415 | -24 |
| 1980-07-13 | vs DET | 82 | W 8-4 | 44-38 | 5 | 31,228 | Bob Ojeda | Dave Rozema | Dick Drago | Dave Rozema | | 399 | 419 | -20 |
| 1980-07-14 | vs DET | 83 | L 4-12 | 44-39 | 5 | 26,044 | Mike Torrez | Bruce Robbins | Bruce Robbins | Mike Torrez | Aurelio Lopez | 403 | 431 | -28 |
| 1980-07-15 | vs KCA | 84 | L 4-8 | 44-40 | 5 | 26,865 | Steve Renko | Rich Gale | Rich Gale | Steve Renko | | 407 | 439 | -32 |
| 1980-07-16 | vs KCA | 85 | L 1-5 | 44-41 | 5 | 27,213 | Dennis Eckersley | Dennis Leonard | Dennis Leonard | Dennis Eckersley | Dan Quisenberry | 408 | 444 | -36 |
| 1980-07-17 | vs KCA | 86 | W 12-4 | 45-41 | 5 | 25,619 | John Tudor | Renie Martin | John Tudor | Renie Martin | | 420 | 448 | -28 |
| 1980-07-18 | vs MIN | 87 | W 1-0 | 46-41 | 5 | 28,116 | Mike Torrez | Roger Erickson | Mike Torrez | Roger Erickson | | 421 | 448 | -27 |
| 1980-07-19 | vs MIN | 88 | L 0-4 | 46-42 | 5 | 32,820 | Bob Ojeda | Fernando Arroyo | Fernando Arroyo | Bob Ojeda | | 421 | 452 | -31 |
| 1980-07-20 | vs MIN | 89 | L 4-5 | 46-43 | 5 | 28,493 | Steve Renko | Jerry Koosman | Doug Corbett | Dick Drago | | 425 | 457 | -32 |
| 1980-07-21 | vs TEX | 90 | L 3-5 | 46-44 | 5 | 24,953 | Dennis Eckersley | Jon Matlack | Jon Matlack | Dennis Eckersley | | 428 | 462 | -34 |
| 1980-07-22 | vs TEX | 91 | L 3-4 | 46-45 | 5 | 24,076 | Mike Torrez | Gaylord Perry | Danny Darwin | Mike Torrez | | 431 | 466 | -35 |
| 1980-07-23 | vs TEX | 92 | W 12-5 | 47-45 | 5 | 25,055 | Bob Stanley | Doc Medich | Dick Drago | John Henry Johnson | | 443 | 471 | -28 |
| 1980-07-25 | @ MIN | 93 | W 7-5 | 48-46 | 5 | 0 | Bob Ojeda | Jerry Koosman | Win Remmerswaal | Jerry Koosman | Tom Burgmeier | 450 | 476 | -26 |
| 1980-07-25 | @ MIN | 94 | L 0-6 | 48-46 | 5 | 23,998 | Steve Renko | Geoff Zahn | Geoff Zahn | Steve Renko | | 450 | 482 | -32 |
| 1980-07-26 | @ MIN | 95 | W 5-1 | 49-46 | 5 | 18,961 | Dennis Eckersley | Roger Erickson | Dennis Eckersley | Roger Erickson | | 455 | 483 | -28 |
| 1980-07-27 | @ MIN | 96 | L 4-5 | 49-47 | 5 | 26,008 | Mike Torrez | Fernando Arroyo | Albert Williams | Mike Torrez | Doug Corbett | 459 | 488 | -29 |
| 1980-07-29 | @ KCA | 97 | L 8-9 | 49-48 | 6 | 35,042 | Bob Ojeda | Paul Splittorff | Dan Quisenberry | Tom Burgmeier | | 467 | 497 | -30 |
| 1980-07-30 | @ KCA | 98 | W 7-1 | 50-48 | 6 | 31,468 | Steve Renko | Steve Busby | Bob Stanley | Steve Busby | | 474 | 498 | -24 |
| 1980-07-31 | @ KCA | 99 | L 3-13 | 50-49 | 6 | 33,500 | Dennis Eckersley | Dennis Leonard | Dennis Leonard | Dennis Eckersley | | 477 | 511 | -34 |
| 1980-08-01 | @ TEX | 100 | L 5-7 | 50-50 | 6 | 18,325 | Mike Torrez | Doc Medich | Doc Medich | Win Remmerswaal | Danny Darwin | 482 | 518 | -36 |
| 1980-08-02 | @ TEX | 101 | W 1-0 | 51-50 | 6 | 24,722 | Bob Ojeda | Ed Figueroa | Bob Ojeda | Ed Figueroa | Bob Stanley | 483 | 518 | -35 |
| 1980-08-03 | @ TEX | 102 | W 6-4 | 52-50 | 5 | 32,015 | Mike Torrez | Jon Matlack | Mike Torrez | Jon Matlack | Skip Lockwood | 489 | 522 | -33 |
| 1980-08-04 | vs MIL | 103 | W 7-2 | 53-50 | 5 | 27,864 | Steve Renko | Reggie Cleveland | Steve Renko | Reggie Cleveland | Bob Stanley | 496 | 524 | -28 |
| 1980-08-05 | vs MIL | 104 | W 3-1 | 54-50 | 5 | 27,996 | Dennis Eckersley | Mike Caldwell | Dennis Eckersley | Mike Caldwell | Tom Burgmeier | 499 | 525 | -26 |
| 1980-08-06 | vs MIL | 105 | L 4-9 | 54-51 | 6 | 28,033 | Bob Ojeda | Lary Sorensen | Lary Sorensen | Dick Drago | Bill Castro | 503 | 534 | -31 |
| 1980-08-07 | vs MIL | 106 | W 7-3 | 55-51 | 6 | 27,966 | Mike Torrez | Paul Mitchell | Mike Torrez | Paul Mitchell | Bob Stanley | 510 | 537 | -27 |
| 1980-08-08 | vs CHA | 107 | W 4-1 | 56-51 | 5 | 29,326 | Skip Lockwood | Richard Dotson | Bill Campbell | Richard Dotson | Bob Stanley | 514 | 538 | -24 |
| 1980-08-09 | vs CHA | 108 | L 4-5 | 56-52 | 5 | 32,719 | Steve Renko | Mike Proly | Mike Proly | Steve Renko | Ed Farmer | 518 | 543 | -25 |
| 1980-08-10 | vs CHA | 109 | W 4-3 | 57-52 | 5 | 30,124 | Dennis Eckersley | LaMarr Hoyt | Dennis Eckersley | LaMarr Hoyt | Bob Stanley | 522 | 546 | -24 |
| 1980-08-11 | @ DET | 110 | L 7-8 | 57-53 | 5 | 28,222 | Bob Ojeda | Jack Morris | Aurelio Lopez | Tom Burgmeier | | 529 | 554 | -25 |
| 1980-08-12 | @ DET | 111 | W 5-4 | 58-53 | 4 | 48,361 | Mike Torrez | Mark Fidrych | Bill Campbell | Mark Fidrych | Bob Stanley | 534 | 558 | -24 |
| 1980-08-13 | @ DET | 112 | L 1-2 | 58-54 | 6 | 24,565 | John Tudor | Dan Petry | Dan Petry | John Tudor | Aurelio Lopez | 535 | 560 | -25 |
| 1980-08-14 | @ DET | 113 | W 3-1 | 59-54 | 6 | 25,579 | Steve Renko | Dan Schatzeder | Steve Renko | Dan Schatzeder | Bob Stanley | 538 | 561 | -23 |
| 1980-08-15 | @ CHA | 114 | W 8-5 | 60-54 | 5 | 22,521 | Dennis Eckersley | Mike Proly | Dennis Eckersley | Mike Proly | Bob Stanley | 546 | 566 | -20 |
| 1980-08-19 | @ OAK | 115 | W 7-5 | 61-54 | 4 | 11,934 | Mike Torrez | Matt Keough | Bob Stanley | Craig Minetto | Tom Burgmeier | 553 | 571 | -18 |
| 1980-08-20 | @ OAK | 116 | L 1-2 | 61-55 | 4 | 7,569 | Dennis Eckersley | Mike Norris | Mike Norris | Dennis Eckersley | Bob Lacey | 554 | 573 | -19 |
| 1980-08-21 | @ OAK | 117 | W 5-1 | 62-55 | 4 | 11,357 | John Tudor | Rick Langford | John Tudor | Rick Langford | | 559 | 574 | -15 |
| 1980-08-22 | @ SEA | 118 | W 1-0 | 63-55 | 4 | 10,792 | Steve Renko | Jim Beattie | Steve Renko | Jim Beattie | Bob Stanley | 560 | 574 | -14 |
| 1980-08-23 | @ SEA | 119 | L 1-3 | 63-56 | 4 | 16,072 | Bruce Hurst | Rob Dressler | Rob Dressler | Bruce Hurst | Shane Rawley | 561 | 577 | -16 |
| 1980-08-24 | @ SEA | 120 | W 10-7 | 64-56 | 3 | 16,920 | Mike Torrez | Rick Honeycutt | Bill Campbell | Rick Honeycutt | | 571 | 584 | -13 |
| 1980-08-25 | @ CAL | 121 | W 4-2 | 65-56 | 3 | 25,653 | Dennis Eckersley | Frank Tanana | Bob Stanley | Mark Clear | | 575 | 586 | -11 |
| 1980-08-26 | @ CAL | 122 | W 5-1 | 66-56 | 3 | 29,007 | John Tudor | Chris Knapp | John Tudor | Chris Knapp | Bob Stanley | 580 | 587 | -7 |
| 1980-08-28 | vs OAK | 123 | W 3-2 | 67-56 | 3 | 28,262 | Steve Renko | Steve McCatty | Tom Burgmeier | Steve McCatty | Bob Stanley | 583 | 589 | -6 |
| 1980-08-29 | vs OAK | 124 | W 6-3 | 68-56 | 3 | 28,666 | Mike Torrez | Brian Kingman | Mike Torrez | Brian Kingman | Tom Burgmeier | 589 | 592 | -3 |
| 1980-08-30 | vs OAK | 125 | W 7-6 | 69-56 | 3 | 27,146 | Dennis Eckersley | Matt Keough | Bill Campbell | Bob Lacey | | 596 | 598 | -2 |
| 1980-08-31 | vs OAK | 126 | W 5-1 | 70-56 | 3 | 32,022 | John Tudor | Mike Norris | John Tudor | Mike Norris | Bob Stanley | 601 | 599 | 2 |
| 1980-09-01 | vs CAL | 127 | W 4-3 | 71-56 | 3 | 23,877 | Dick Drago | Dave Frost | Dick Drago | Dave Frost | Tom Burgmeier | 605 | 602 | 3 |
| 1980-09-02 | vs CAL | 128 | W 10-2 | 72-56 | 3 | 19,693 | Steve Renko | Jim Dorsey | Steve Renko | Jim Dorsey | | 615 | 604 | 11 |
| 1980-09-03 | vs CAL | 129 | L 2-7 | 72-57 | 3 | 22,340 | Mike Torrez | Alfredo Martinez | Alfredo Martinez | Mike Torrez | | 617 | 611 | 6 |
| 1980-09-04 | vs SEA | 130 | L 4-7 | 72-58 | 3 | 18,256 | Dennis Eckersley | Glenn Abbott | Glenn Abbott | Dennis Eckersley | Manny Sarmiento | 621 | 618 | 3 |
| 1980-09-05 | vs SEA | 131 | L 2-4 | 72-59 | 3 | 20,420 | John Tudor | Floyd Bannister | Floyd Bannister | John Tudor | Shane Rawley | 623 | 622 | 1 |
| 1980-09-06 | vs SEA | 132 | W 5-1 | 73-59 | 3 | 23,317 | Dick Drago | Mike Parrott | Dick Drago | Mike Parrott | Tom Burgmeier | 628 | 623 | 5 |
| 1980-09-07 | vs SEA | 133 | L 6-12 | 73-60 | 3 | 23,360 | Steve Renko | Rick Anderson | Byron McLaughlin | Steve Renko | | 634 | 635 | -1 |
| 1980-09-08 | @ CLE | 134 | W 10-4 | 74-60 | 3 | 5,506 | Mike Torrez | Dan Spillner | Mike Torrez | Dan Spillner | | 644 | 639 | 5 |
| 1980-09-09 | @ CLE | 135 | W 4-3 | 75-60 | 3 | 5,182 | Dennis Eckersley | Ross Grimsley | Dennis Eckersley | Victor Cruz | Tom Burgmeier | 648 | 642 | 6 |
| 1980-09-10 | @ CLE | 136 | L 4-7 | 75-61 | 3 | 5,242 | John Tudor | Rick Waits | Rick Waits | John Tudor | | 652 | 649 | 3 |
| 1980-09-11 | vs NYA | 137 | L 5-8 | 75-62 | 3 | 32,979 | Dick Drago | Luis Tiant | Ron Davis | Tom Burgmeier | | 657 | 657 | 0 |
| 1980-09-12 | vs NYA | 138 | L 2-4 | 75-63 | 3 | 33,787 | Steve Renko | Rudy May | Rudy May | Steve Renko | Rich Gossage | 659 | 661 | -2 |
| 1980-09-13 | vs NYA | 139 | L 3-4 | 75-64 | 3 | 33,375 | Mike Torrez | Tommy John | Tommy John | Mike Torrez | | 662 | 665 | -3 |
| 1980-09-14 | vs NYA | 140 | L 3-5 | 75-65 | 3 | 33,296 | Dennis Eckersley | Gaylord Perry | Ron Davis | Dennis Eckersley | | 665 | 670 | -5 |
| 1980-09-16 | vs CLE | 141 | W 9-5 | 76-65 | 3 | 14,630 | John Tudor | Ross Grimsley | John Tudor | Ross Grimsley | Bob Stanley | 674 | 675 | -1 |
| 1980-09-17 | vs CLE | 142 | L 5-6 | 76-66 | 3 | 15,321 | Dick Drago | Len Barker | Dan Spillner | Mike Torrez | | 679 | 681 | -2 |
| 1980-09-18 | vs CLE | 143 | W 8-3 | 77-66 | 3 | 14,845 | Steve Crawford | Wayne Garland | Steve Crawford | Wayne Garland | | 687 | 684 | 3 |
| 1980-09-19 | @ NYA | 144 | L 1-2 | 77-67 | 4 | 50,505 | Steve Renko | Luis Tiant | Luis Tiant | Steve Renko | Rich Gossage | 688 | 686 | 2 |
| 1980-09-20 | @ NYA | 145 | W 4-1 | 78-67 | 4 | 50,257 | Dennis Eckersley | Gaylord Perry | Dennis Eckersley | Gaylord Perry | | 692 | 687 | 5 |
| 1980-09-21 | @ NYA | 146 | L 0-3 | 78-68 | 4 | 54,033 | John Tudor | Ron Guidry | Ron Guidry | John Tudor | Rich Gossage | 692 | 690 | 2 |
| 1980-09-22 | @ BAL | 147 | W 5-3 | 79-68 | 3 | 23,260 | Dick Drago | Scott McGregor | Dick Drago | Scott McGregor | Tom Burgmeier | 697 | 693 | 4 |
| 1980-09-23 | @ BAL | 148 | L 6-8 | 79-69 | 3 | 20,798 | Steve Crawford | Jim Palmer | Tim Stoddard | Bob Stanley | | 703 | 701 | 2 |
| 1980-09-24 | @ BAL | 149 | L 9-12 | 79-70 | 4 | 21,436 | Steve Renko | Steve Stone | Tippy Martinez | Mike Torrez | Tim Stoddard | 712 | 713 | -1 |
| 1980-09-26 | @ TOR | 150 | W 3-1 | 80-70 | 4 | 15,187 | Dennis Eckersley | Dave Stieb | Dennis Eckersley | Dave Stieb | | 715 | 714 | 1 |
| 1980-09-27 | @ TOR | 151 | W 4-3 | 81-70 | 3 | 21,533 | John Tudor | Jim Clancy | Bob Stanley | Jim Clancy | Tom Burgmeier | 719 | 717 | 2 |
| 1980-09-28 | @ TOR | 152 | W 7-3 | 82-70 | 3 | 32,042 | Steve Crawford | Joey McLaughlin | Steve Crawford | Joey McLaughlin | | 726 | 720 | 6 |
| 1980-09-29 | vs BAL | 153 | L 2-5 | 82-72 | 3 | 0 | Dick Drago | Dennis Martinez | Dennis Martinez | Dick Drago | | 728 | 725 | 3 |
| 1980-09-29 | vs BAL | 154 | L 3-4 | 82-72 | 3 | 23,002 | Keith MacWhorter | Steve Stone | Steve Stone | Keith MacWhorter | Sammy Stewart | 731 | 729 | 2 |
| 1980-09-30 | vs BAL | 155 | L 6-11 | 82-73 | 3 | 18,393 | Steve Renko | Mike Flanagan | Mike Flanagan | Steve Renko | | 737 | 740 | -3 |
| 1980-10-01 | vs BAL | 156 | L 8-12 | 82-74 | 5 | 16,781 | Dennis Eckersley | Scott McGregor | Sammy Stewart | Dennis Eckersley | Dennis Martinez | 745 | 752 | -7 |
| 1980-10-02 | vs TOR | 157 | W 4-1 | 83-74 | 4 | 11,872 | John Tudor | Jim Clancy | John Tudor | Jim Clancy | | 749 | 753 | -4 |
| 1980-10-04 | vs TOR | 158 | L 6-7 | 83-76 | 5 | 0 | Steve Crawford | Joey McLaughlin | Luis Leal | Bob Stanley | Mike Barlow | 755 | 760 | -5 |
| 1980-10-04 | vs TOR | 159 | L 1-3 | 83-76 | 5 | 14,179 | Dick Drago | Paul Mirabella | Paul Mirabella | Dick Drago | | 756 | 763 | -7 |
| 1980-10-05 | vs TOR | 160 | L 1-4 | 83-77 | 5 | 16,562 | Keith MacWhorter | Jackson Todd | Jackson Todd | Keith MacWhorter | | 757 | 767 | -10 |