| 1980-04-10 | vs NYA | 1 | W 1-0 | 1-0 | 3 | 33,196 | Jon Matlack | Ron Guidry | Sparky Lyle | Tom Underwood | | 1 | 0 | 1 |
| 1980-04-11 | vs NYA | 2 | W 11-7 | 2-0 | 1 | 21,424 | Fergie Jenkins | Tommy John | Fergie Jenkins | Ron Davis | Dave Rajsich | 12 | 7 | 5 |
| 1980-04-13 | vs NYA | 3 | L 4-9 | 2-2 | 7 | 0 | Steve Comer | Luis Tiant | Luis Tiant | Steve Comer | | 16 | 16 | 0 |
| 1980-04-13 | vs NYA | 4 | L 2-8 | 2-2 | 7 | 13,882 | Gaylord Perry | Ed Figueroa | Ed Figueroa | Gaylord Perry | Tom Underwood | 18 | 24 | -6 |
| 1980-04-14 | vs CLE | 5 | W 7-4 | 3-2 | 5 | 8,656 | Doc Medich | Rick Waits | Doc Medich | Rick Waits | Sparky Lyle | 25 | 28 | -3 |
| 1980-04-15 | vs CLE | 6 | W 3-0 | 4-2 | 3 | 11,895 | Jon Matlack | Bob Owchinko | Jon Matlack | Bob Owchinko | | 28 | 28 | 0 |
| 1980-04-16 | vs CLE | 7 | W 8-7 | 5-2 | 1 | 11,557 | Fergie Jenkins | Len Barker | Jim Kern | Victor Cruz | | 36 | 35 | 1 |
| 1980-04-18 | @ BOS | 8 | W 6-5 | 6-2 | 1 | 10,580 | Steve Comer | Bob Stanley | Danny Darwin | Skip Lockwood | Jim Kern | 42 | 40 | 2 |
| 1980-04-19 | @ BOS | 9 | W 8-0 | 7-2 | 1 | 22,715 | Gaylord Perry | Dennis Eckersley | Gaylord Perry | Dennis Eckersley | | 50 | 40 | 10 |
| 1980-04-20 | @ BOS | 10 | L 5-6 | 7-3 | 3 | 23,696 | Doc Medich | Chuck Rainey | Tom Burgmeier | Jim Kern | | 55 | 46 | 9 |
| 1980-04-21 | vs DET | 11 | W 3-2 | 8-3 | 2 | 14,834 | Jon Matlack | Milt Wilcox | Jon Matlack | Milt Wilcox | Sparky Lyle | 58 | 48 | 10 |
| 1980-04-22 | vs DET | 12 | L 0-2 | 8-4 | 3 | 14,650 | Fergie Jenkins | Dave Rozema | Dave Rozema | Fergie Jenkins | | 58 | 50 | 8 |
| 1980-04-23 | vs DET | 13 | L 4-5 | 8-5 | 3 | 13,334 | Steve Comer | Jack Morris | Jack Morris | Steve Comer | Aurelio Lopez | 62 | 55 | 7 |
| 1980-04-25 | @ CLE | 14 | W 4-1 | 9-5 | 3 | 7,126 | Gaylord Perry | Rick Waits | Danny Darwin | Rick Waits | | 66 | 56 | 10 |
| 1980-04-26 | @ CLE | 15 | L 7-8 | 9-6 | 3 | 7,092 | Jon Matlack | John Denny | Victor Cruz | Jim Kern | Mike Stanton | 73 | 64 | 9 |
| 1980-04-27 | @ CLE | 16 | L 4-7 | 9-7 | 4 | 12,879 | Fergie Jenkins | Len Barker | Len Barker | Fergie Jenkins | | 77 | 71 | 6 |
| 1980-04-29 | @ DET | 17 | W 10-5 | 10-7 | 3 | 7,941 | Steve Comer | Jack Morris | Steve Comer | Jack Morris | Dave Rajsich | 87 | 76 | 11 |
| 1980-04-30 | @ DET | 18 | L 4-5 | 10-8 | 4 | 8,056 | Gaylord Perry | Dan Schatzeder | Milt Wilcox | Sparky Lyle | | 91 | 81 | 10 |
| 1980-05-02 | vs BAL | 19 | L 5-7 | 10-9 | 4 | 21,962 | Jon Matlack | Mike Flanagan | Mike Flanagan | Jim Kern | Tim Stoddard | 96 | 88 | 8 |
| 1980-05-03 | vs BAL | 20 | W 3-2 | 11-9 | 3 | 25,402 | Fergie Jenkins | Jim Palmer | Fergie Jenkins | Jim Palmer | | 99 | 90 | 9 |
| 1980-05-04 | vs BAL | 21 | L 5-9 | 11-10 | 4 | 14,653 | Steve Comer | Dennis Martinez | Dennis Martinez | Steve Comer | Dave Ford | 104 | 99 | 5 |
| 1980-05-05 | vs BOS | 22 | W 11-3 | 12-10 | 3 | 12,702 | Gaylord Perry | Dennis Eckersley | Gaylord Perry | Dennis Eckersley | | 115 | 102 | 13 |
| 1980-05-06 | vs BOS | 23 | W 7-2 | 13-10 | 3 | 11,349 | Doc Medich | Bruce Hurst | Doc Medich | Bruce Hurst | | 122 | 104 | 18 |
| 1980-05-07 | vs BOS | 24 | L 4-7 | 13-11 | 3 | 13,866 | Jon Matlack | Mike Torrez | Dick Drago | Adrian Devine | | 126 | 111 | 15 |
| 1980-05-09 | vs CHA | 25 | W 2-1 | 14-11 | 2 | 23,600 | Fergie Jenkins | Ross Baumgarten | Jim Kern | Mike Proly | | 128 | 112 | 16 |
| 1980-05-10 | vs CHA | 26 | L 6-10 | 14-12 | 4 | 24,327 | Gaylord Perry | Richard Dotson | Ed Farmer | Danny Darwin | | 134 | 122 | 12 |
| 1980-05-11 | vs CHA | 27 | W 5-1 | 15-12 | 2 | 17,849 | Doc Medich | Rich Wortham | Doc Medich | Rich Wortham | | 139 | 123 | 16 |
| 1980-05-12 | @ BAL | 28 | W 5-1 | 16-12 | 2 | 13,184 | Jon Matlack | Dave Ford | Jon Matlack | Dave Ford | | 144 | 124 | 20 |
| 1980-05-13 | @ BAL | 29 | L 2-4 | 16-13 | 4 | 12,707 | Fergie Jenkins | Steve Stone | Steve Stone | Fergie Jenkins | Tim Stoddard | 146 | 128 | 18 |
| 1980-05-14 | @ BAL | 30 | W 6-3 | 17-13 | 2 | 16,762 | Gaylord Perry | Scott McGregor | Gaylord Perry | Paul Hartzell | Sparky Lyle | 152 | 131 | 21 |
| 1980-05-16 | @ NYA | 31 | L 2-6 | 17-14 | 2 | 30,068 | Doc Medich | Tommy John | Tommy John | Doc Medich | | 154 | 137 | 17 |
| 1980-05-17 | @ NYA | 32 | L 0-3 | 17-15 | 4 | 28,173 | Jon Matlack | Tom Underwood | Tom Underwood | Jon Matlack | | 154 | 140 | 14 |
| 1980-05-18 | @ NYA | 33 | W 5-4 | 18-15 | 4 | 48,030 | Fergie Jenkins | Mike Griffin | Sparky Lyle | Ron Davis | | 159 | 144 | 15 |
| 1980-05-19 | vs CAL | 34 | L 2-3 | 18-16 | 4 | 15,833 | Gaylord Perry | Dave Frost | Mark Clear | Jim Kern | | 161 | 147 | 14 |
| 1980-05-20 | vs CAL | 35 | L 4-5 | 18-17 | 4 | 16,803 | Doc Medich | Alfredo Martinez | Alfredo Martinez | Doc Medich | Dave LaRoche | 165 | 152 | 13 |
| 1980-05-21 | vs CAL | 36 | L 8-9 | 18-18 | 4 | 16,232 | Steve Comer | Bruce Kison | Mark Clear | Jim Kern | | 173 | 161 | 12 |
| 1980-05-22 | vs CAL | 37 | W 12-6 | 19-18 | 4 | 15,308 | Jon Matlack | Don Aase | Danny Darwin | Don Aase | | 185 | 167 | 18 |
| 1980-05-23 | @ OAK | 38 | W 3-1 | 20-18 | 3 | 4,141 | Fergie Jenkins | Rick Langford | Fergie Jenkins | Rick Langford | | 188 | 168 | 20 |
| 1980-05-24 | @ OAK | 39 | L 7-15 | 20-19 | 4 | 5,061 | Gaylord Perry | Steve McCatty | Steve McCatty | Gaylord Perry | | 195 | 183 | 12 |
| 1980-05-25 | @ OAK | 40 | W 7-3 | 21-19 | 3 | 10,549 | Doc Medich | Mike Norris | Doc Medich | Mike Norris | Jim Kern | 202 | 186 | 16 |
| 1980-05-26 | @ CAL | 41 | W 6-5 | 22-19 | 3 | 34,708 | Danny Darwin | Bruce Kison | Adrian Devine | Mark Clear | Sparky Lyle | 208 | 191 | 17 |
| 1980-05-27 | @ CAL | 42 | L 0-2 | 22-20 | 3 | 22,935 | Fergie Jenkins | Don Aase | Don Aase | Fergie Jenkins | | 208 | 193 | 15 |
| 1980-05-28 | @ CAL | 43 | L 6-7 | 22-21 | 4 | 24,531 | Jon Matlack | Alfredo Martinez | Mark Clear | Jim Kern | Chris Knapp | 214 | 200 | 14 |
| 1980-05-30 | vs OAK | 44 | L 3-6 | 22-22 | 5 | 26,613 | Gaylord Perry | Steve McCatty | Steve McCatty | Gaylord Perry | | 217 | 206 | 11 |
| 1980-05-31 | vs OAK | 45 | L 3-4 | 22-23 | 5 | 24,305 | Doc Medich | Mike Norris | Mike Norris | Doc Medich | Bob Lacey | 220 | 210 | 10 |
| 1980-06-01 | vs OAK | 46 | W 7-3 | 23-23 | 5 | 17,892 | Danny Darwin | Matt Keough | Danny Darwin | Matt Keough | | 227 | 213 | 14 |
| 1980-06-02 | @ CHA | 47 | L 1-1 | 23-24 | 5 | 10,586 | Jon Matlack | Ross Baumgarten | | | | 228 | 214 | 14 |
| 1980-06-03 | @ CHA | 48 | L 4-5 | 23-25 | 5 | 12,232 | Gaylord Perry | Ken Kravec | Ed Farmer | Jim Kern | Rich Wortham | 232 | 219 | 13 |
| 1980-06-04 | @ CHA | 49 | W 4-3 | 24-26 | 4 | 0 | Doc Medich | Francisco Barrios | Doc Medich | Francisco Barrios | Sparky Lyle | 236 | 222 | 14 |
| 1980-06-04 | @ CHA | 50 | L 1-5 | 24-26 | 4 | 16,000 | Dave Rajsich | Richard Dotson | Richard Dotson | Dave Rajsich | | 237 | 227 | 10 |
| 1980-06-05 | vs KCA | 51 | L 0-8 | 24-27 | 5 | 16,512 | Jim Kern | Dennis Leonard | Dennis Leonard | Jim Kern | | 237 | 235 | 2 |
| 1980-06-06 | vs KCA | 52 | L 2-4 | 24-28 | 5 | 26,367 | Jon Matlack | Paul Splittorff | Paul Splittorff | Jon Matlack | Dan Quisenberry | 239 | 239 | 0 |
| 1980-06-07 | vs KCA | 53 | L 2-7 | 24-29 | 5 | 24,530 | Gaylord Perry | Rich Gale | Rich Gale | Gaylord Perry | | 241 | 246 | -5 |
| 1980-06-08 | vs KCA | 54 | L 4-5 | 24-30 | 5 | 16,179 | Doc Medich | Larry Gura | Gary Christenson | Bob Babcock | Dan Quisenberry | 245 | 251 | -6 |
| 1980-06-10 | @ MIL | 55 | W 3-1 | 25-30 | 5 | 17,085 | Fergie Jenkins | Moose Haas | Fergie Jenkins | Moose Haas | | 248 | 252 | -4 |
| 1980-06-11 | @ MIL | 56 | L 1-7 | 25-31 | 5 | 23,194 | Jon Matlack | Lary Sorensen | Lary Sorensen | Jon Matlack | | 249 | 259 | -10 |
| 1980-06-12 | @ MIL | 57 | L 1-8 | 25-32 | 5 | 29,140 | Gaylord Perry | Mike Caldwell | Mike Caldwell | Gaylord Perry | | 250 | 267 | -17 |
| 1980-06-13 | @ TOR | 58 | W 6-3 | 26-32 | 5 | 20,034 | Doc Medich | Dave Stieb | Doc Medich | Dave Stieb | Sparky Lyle | 256 | 270 | -14 |
| 1980-06-14 | @ TOR | 59 | L 6-7 | 26-33 | 5 | 24,184 | Brian Allard | Luis Leal | Tom Buskey | Bob Babcock | | 262 | 277 | -15 |
| 1980-06-15 | @ TOR | 60 | L 3-5 | 26-34 | 5 | 30,143 | Fergie Jenkins | Jim Clancy | Jim Clancy | Fergie Jenkins | Jerry Garvin | 265 | 282 | -17 |
| 1980-06-16 | @ KCA | 61 | W 6-3 | 27-34 | 5 | 39,457 | Jon Matlack | Paul Splittorff | Bob Babcock | Dan Quisenberry | Sparky Lyle | 271 | 285 | -14 |
| 1980-06-17 | @ KCA | 62 | L 2-3 | 27-35 | 5 | 25,324 | Gaylord Perry | Rich Gale | Rich Gale | Gaylord Perry | | 273 | 288 | -15 |
| 1980-06-18 | vs MIL | 63 | W 8-1 | 28-35 | 4 | 12,750 | Doc Medich | Rickey Keeton | Doc Medich | Rickey Keeton | | 281 | 289 | -8 |
| 1980-06-19 | vs MIL | 64 | L 4-10 | 28-36 | 4 | 12,763 | Brian Allard | Bill Travers | Bill Travers | Brian Allard | Paul Mitchell | 285 | 299 | -14 |
| 1980-06-20 | vs TOR | 65 | W 5-2 | 29-36 | 4 | 13,747 | Fergie Jenkins | Jim Clancy | Fergie Jenkins | Jerry Garvin | | 290 | 301 | -11 |
| 1980-06-21 | vs TOR | 66 | W 2-1 | 30-36 | 4 | 17,846 | Jon Matlack | Jesse Jefferson | Jon Matlack | Joey McLaughlin | | 292 | 302 | -10 |
| 1980-06-22 | vs TOR | 67 | L 5-6 | 30-37 | 4 | 13,650 | Gaylord Perry | Jack Kucek | Jerry Garvin | Jim Kern | | 297 | 308 | -11 |
| 1980-06-24 | vs SEA | 68 | W 5-4 | 31-37 | 3 | 11,324 | Doc Medich | Glenn Abbott | Sparky Lyle | Shane Rawley | | 302 | 312 | -10 |
| 1980-06-25 | vs SEA | 69 | W 6-1 | 32-37 | 3 | 14,029 | Fergie Jenkins | Mike Parrott | Fergie Jenkins | Mike Parrott | | 308 | 313 | -5 |
| 1980-06-26 | vs SEA | 70 | L 4-8 | 32-38 | 3 | 9,531 | Jon Matlack | Floyd Bannister | Floyd Bannister | Jon Matlack | Shane Rawley | 312 | 321 | -9 |
| 1980-06-27 | vs MIN | 71 | W 5-0 | 33-38 | 3 | 10,818 | Gaylord Perry | Pete Redfern | Gaylord Perry | Pete Redfern | | 317 | 321 | -4 |
| 1980-06-28 | vs MIN | 72 | W 11-3 | 34-38 | 3 | 14,336 | Steve Comer | Jerry Koosman | Steve Comer | Jerry Koosman | Danny Darwin | 328 | 324 | 4 |
| 1980-06-29 | vs MIN | 73 | L 3-5 | 34-39 | 3 | 22,342 | Doc Medich | Roger Erickson | Roger Erickson | Doc Medich | Doug Corbett | 331 | 329 | 2 |
| 1980-06-30 | @ SEA | 74 | W 11-5 | 35-39 | 3 | 5,658 | Fergie Jenkins | Mike Parrott | Fergie Jenkins | Mike Parrott | | 342 | 334 | 8 |
| 1980-07-01 | @ SEA | 75 | L 5-6 | 35-40 | 3 | 6,005 | Jon Matlack | Floyd Bannister | Shane Rawley | Jim Kern | | 347 | 340 | 7 |
| 1980-07-02 | @ SEA | 76 | W 6-3 | 36-40 | 3 | 8,692 | Gaylord Perry | Rick Honeycutt | Gaylord Perry | Rick Honeycutt | | 353 | 343 | 10 |
| 1980-07-03 | @ MIN | 77 | L 3-10 | 36-41 | 3 | 7,612 | Steve Comer | Roger Erickson | Roger Erickson | Steve Comer | Doug Corbett | 356 | 353 | 3 |
| 1980-07-04 | @ MIN | 78 | W 4-3 | 37-41 | 3 | 32,948 | Doc Medich | Darrell Jackson | Danny Darwin | John Verhoeven | | 360 | 356 | 4 |
| 1980-07-05 | @ MIN | 79 | L 1-2 | 37-42 | 3 | 9,398 | Fergie Jenkins | Geoff Zahn | Geoff Zahn | Fergie Jenkins | | 361 | 358 | 3 |
| 1980-07-06 | @ MIN | 80 | L 1-4 | 37-43 | 3 | 9,614 | Jon Matlack | Fernando Arroyo | Fernando Arroyo | Jon Matlack | Jerry Koosman | 362 | 362 | 0 |
| 1980-07-10 | vs NYA | 81 | L 5-13 | 37-44 | 3 | 34,463 | Fergie Jenkins | Ron Guidry | Ron Guidry | Fergie Jenkins | Tim Lollar | 367 | 375 | -8 |
| 1980-07-11 | vs NYA | 82 | W 10-8 | 38-44 | 3 | 32,378 | Jon Matlack | Tom Underwood | Jon Matlack | Tom Underwood | John Henry Johnson | 377 | 383 | -6 |
| 1980-07-12 | vs CLE | 83 | L 8-9 | 38-45 | 5 | 27,784 | Gaylord Perry | Len Barker | Len Barker | Gaylord Perry | Victor Cruz | 385 | 392 | -7 |
| 1980-07-13 | vs CLE | 84 | W 12-2 | 39-45 | 4 | 12,503 | Doc Medich | Dan Spillner | Doc Medich | Dan Spillner | | 397 | 394 | 3 |
| 1980-07-14 | vs CLE | 85 | W 4-2 | 40-45 | 3 | 9,446 | Steve Comer | Rick Waits | Danny Darwin | Rick Waits | | 401 | 396 | 5 |
| 1980-07-15 | vs CHA | 86 | L 1-2 | 40-46 | 4 | 13,777 | Fergie Jenkins | Britt Burns | Britt Burns | Fergie Jenkins | | 402 | 398 | 4 |
| 1980-07-16 | vs CHA | 87 | W 11-3 | 41-46 | 3 | 11,256 | Jon Matlack | Richard Dotson | Jon Matlack | Richard Dotson | Sparky Lyle | 413 | 401 | 12 |
| 1980-07-17 | vs CHA | 88 | W 3-2 | 42-46 | 2 | 13,489 | Gaylord Perry | Ross Baumgarten | Danny Darwin | Mike Proly | | 416 | 403 | 13 |
| 1980-07-18 | @ BAL | 89 | L 7-8 | 42-47 | 2 | 22,659 | Doc Medich | Mike Flanagan | Mike Flanagan | Jim Kern | Tippy Martinez | 423 | 411 | 12 |
| 1980-07-19 | @ BAL | 90 | W 11-8 | 43-47 | 2 | 27,277 | Steve Comer | Scott McGregor | Danny Darwin | Sammy Stewart | | 434 | 419 | 15 |
| 1980-07-20 | @ BAL | 91 | W 7-1 | 44-47 | 2 | 20,012 | Fergie Jenkins | Jim Palmer | Fergie Jenkins | Jim Palmer | | 441 | 420 | 21 |
| 1980-07-21 | @ BOS | 92 | W 5-3 | 45-47 | 2 | 24,953 | Jon Matlack | Dennis Eckersley | Jon Matlack | Dennis Eckersley | | 446 | 423 | 23 |
| 1980-07-22 | @ BOS | 93 | W 4-3 | 46-47 | 2 | 24,076 | Gaylord Perry | Mike Torrez | Danny Darwin | Mike Torrez | | 450 | 426 | 24 |
| 1980-07-23 | @ BOS | 94 | L 5-12 | 46-48 | 2 | 25,055 | Doc Medich | Bob Stanley | Dick Drago | John Henry Johnson | | 455 | 438 | 17 |
| 1980-07-25 | @ CHA | 95 | W 6-4 | 47-48 | 2 | 22,491 | Steve Comer | Richard Dotson | Jim Kern | Ed Farmer | | 461 | 442 | 19 |
| 1980-07-26 | @ CHA | 96 | L 3-4 | 47-50 | 2 | 0 | Fergie Jenkins | LaMarr Hoyt | LaMarr Hoyt | Fergie Jenkins | | 464 | 446 | 18 |
| 1980-07-26 | @ CHA | 97 | L 1-1 | 47-50 | 2 | 21,503 | Gaylord Perry | Britt Burns | | | | 465 | 447 | 18 |
| 1980-07-27 | @ CHA | 98 | L 2-3 | 48-51 | 2 | 0 | Doc Medich | Steve Trout | Steve Trout | Doc Medich | Mike Proly | 467 | 450 | 17 |
| 1980-07-27 | @ CHA | 99 | W 4-3 | 48-51 | 2 | 12,364 | Jon Matlack | Rich Wortham | Charlie Hough | Mike Proly | | 471 | 453 | 18 |
| 1980-07-29 | vs BAL | 100 | L 3-4 | 48-52 | 3 | 15,808 | Charlie Hough | Scott McGregor | Scott McGregor | Charlie Hough | Tippy Martinez | 474 | 457 | 17 |
| 1980-07-30 | vs BAL | 101 | L 2-3 | 48-53 | 3 | 12,704 | Gaylord Perry | Jim Palmer | Jim Palmer | Gaylord Perry | Tim Stoddard | 476 | 460 | 16 |
| 1980-07-31 | vs BAL | 102 | W 7-4 | 49-53 | 3 | 14,969 | Fergie Jenkins | Steve Stone | Fergie Jenkins | Steve Stone | Danny Darwin | 483 | 464 | 19 |
| 1980-08-01 | vs BOS | 103 | W 7-5 | 50-53 | 3 | 18,325 | Doc Medich | Mike Torrez | Doc Medich | Win Remmerswaal | Danny Darwin | 490 | 469 | 21 |
| 1980-08-02 | vs BOS | 104 | L 0-1 | 50-54 | 3 | 24,722 | Ed Figueroa | Bob Ojeda | Bob Ojeda | Ed Figueroa | Bob Stanley | 490 | 470 | 20 |
| 1980-08-03 | vs BOS | 105 | L 4-6 | 50-55 | 3 | 32,015 | Jon Matlack | Mike Torrez | Mike Torrez | Jon Matlack | Skip Lockwood | 494 | 476 | 18 |
| 1980-08-04 | @ NYA | 106 | L 4-10 | 50-56 | 3 | 28,603 | Gaylord Perry | Tom Underwood | Tom Underwood | Gaylord Perry | Tim Lollar | 498 | 486 | 12 |
| 1980-08-05 | @ NYA | 107 | W 8-1 | 51-56 | 3 | 38,337 | Fergie Jenkins | Tommy John | Fergie Jenkins | Tommy John | | 506 | 487 | 19 |
| 1980-08-06 | @ NYA | 108 | L 1-2 | 51-57 | 3 | 34,746 | Doc Medich | Rudy May | Rudy May | Doc Medich | Rich Gossage | 507 | 489 | 18 |
| 1980-08-08 | vs DET | 109 | L 0-8 | 51-58 | 3 | 14,138 | Ed Figueroa | Dan Petry | Dan Petry | Ed Figueroa | | 507 | 497 | 10 |
| 1980-08-09 | vs DET | 110 | W 4-3 | 52-58 | 3 | 19,021 | Jon Matlack | Dan Schatzeder | Danny Darwin | Aurelio Lopez | | 511 | 500 | 11 |
| 1980-08-10 | vs DET | 111 | W 4-2 | 53-58 | 3 | 11,752 | Gaylord Perry | Roger Weaver | Gaylord Perry | Roger Weaver | Danny Darwin | 515 | 502 | 13 |
| 1980-08-12 | @ CLE | 112 | L 1-2 | 53-59 | 3 | 9,960 | Fergie Jenkins | Rick Waits | Rick Waits | Fergie Jenkins | Victor Cruz | 516 | 504 | 12 |
| 1980-08-13 | @ CLE | 113 | L 3-14 | 53-60 | 3 | 13,449 | Doc Medich | Wayne Garland | Wayne Garland | Doc Medich | | 519 | 518 | 1 |
| 1980-08-14 | @ CLE | 114 | L 2-7 | 53-61 | 3 | 10,888 | Ed Figueroa | Len Barker | Len Barker | Ed Figueroa | | 521 | 525 | -4 |
| 1980-08-15 | @ DET | 115 | W 6-2 | 54-61 | 3 | 30,247 | Jon Matlack | Pat Underwood | Jon Matlack | Pat Underwood | | 527 | 527 | 0 |
| 1980-08-16 | @ DET | 116 | W 12-5 | 55-61 | 3 | 33,868 | Ken Clay | Jack Morris | Ken Clay | Jack Morris | Danny Darwin | 539 | 532 | 7 |
| 1980-08-17 | @ DET | 117 | W 9-3 | 57-61 | 3 | 0 | Fergie Jenkins | Mark Fidrych | Fergie Jenkins | Mark Fidrych | | 548 | 535 | 13 |
| 1980-08-17 | @ DET | 118 | W 12-6 | 57-61 | 3 | 42,117 | Doc Medich | Milt Wilcox | Doc Medich | Milt Wilcox | | 560 | 541 | 19 |
| 1980-08-18 | vs KCA | 119 | L 3-6 | 57-62 | 3 | 17,609 | Ed Figueroa | Rich Gale | Rich Gale | Ed Figueroa | Dan Quisenberry | 563 | 547 | 16 |
| 1980-08-19 | vs KCA | 120 | L 3-4 | 57-63 | 3 | 17,800 | Jon Matlack | Dennis Leonard | Jeff Twitty | Danny Darwin | Dan Quisenberry | 566 | 551 | 15 |
| 1980-08-20 | vs KCA | 121 | L 3-5 | 57-64 | 3 | 16,996 | Ken Clay | Larry Gura | Dan Quisenberry | John Henry Johnson | Renie Martin | 569 | 556 | 13 |
| 1980-08-22 | vs MIL | 122 | W 12-6 | 58-65 | 3 | 0 | Fergie Jenkins | Reggie Cleveland | Dave Rajsich | Reggie Cleveland | Danny Darwin | 581 | 562 | 19 |
| 1980-08-22 | vs MIL | 123 | L 3-8 | 58-65 | 3 | 15,514 | Doc Medich | Paul Mitchell | Paul Mitchell | Doc Medich | Bob McClure | 584 | 570 | 14 |
| 1980-08-23 | vs MIL | 124 | W 7-5 | 59-65 | 3 | 10,632 | Ed Figueroa | Lary Sorensen | Danny Darwin | Jerry Augustine | | 591 | 575 | 16 |
| 1980-08-24 | vs MIL | 125 | W 4-3 | 60-65 | 3 | 8,425 | Jon Matlack | Bill Travers | John Henry Johnson | Reggie Cleveland | | 595 | 578 | 17 |
| 1980-08-25 | @ TOR | 126 | W 5-1 | 61-65 | 3 | 15,517 | Ken Clay | Jackson Todd | Ken Clay | Jackson Todd | John Henry Johnson | 600 | 579 | 21 |
| 1980-08-26 | @ TOR | 127 | W 8-0 | 62-65 | 3 | 15,478 | Charlie Hough | Jesse Jefferson | Charlie Hough | Jesse Jefferson | | 608 | 579 | 29 |
| 1980-08-27 | @ TOR | 128 | L 4-6 | 62-66 | 3 | 15,442 | Doc Medich | Jim Clancy | Jim Clancy | Doc Medich | Jerry Garvin | 612 | 585 | 27 |
| 1980-08-28 | @ KCA | 129 | W 10-6 | 63-66 | 3 | 25,944 | Fergie Jenkins | Rich Gale | Dave Rajsich | Jeff Twitty | | 622 | 591 | 31 |
| 1980-08-29 | @ KCA | 130 | L 3-7 | 63-67 | 3 | 32,781 | Ed Figueroa | Dennis Leonard | Dennis Leonard | Ed Figueroa | | 625 | 598 | 27 |
| 1980-08-30 | @ KCA | 131 | W 7-5 | 64-67 | 3 | 34,557 | Jon Matlack | Larry Gura | John Henry Johnson | Dan Quisenberry | | 632 | 603 | 29 |
| 1980-08-31 | @ KCA | 132 | L 3-4 | 64-68 | 3 | 37,390 | Ken Clay | Paul Splittorff | Dan Quisenberry | Sparky Lyle | | 635 | 607 | 28 |
| 1980-09-01 | vs TOR | 133 | W 9-1 | 65-68 | 3 | 8,224 | Doc Medich | Joey McLaughlin | Doc Medich | Joey McLaughlin | | 644 | 608 | 36 |
| 1980-09-02 | vs TOR | 134 | W 3-2 | 66-68 | 2 | 6,903 | Fergie Jenkins | Luis Leal | Fergie Jenkins | Luis Leal | | 647 | 610 | 37 |
| 1980-09-03 | vs TOR | 135 | L 2-4 | 66-69 | 2 | 6,984 | Ed Figueroa | Dave Stieb | Dave Stieb | Ed Figueroa | | 649 | 614 | 35 |
| 1980-09-05 | @ MIL | 136 | W 6-5 | 67-69 | 2 | 25,076 | Jon Matlack | Moose Haas | Jon Matlack | Moose Haas | Danny Darwin | 655 | 619 | 36 |
| 1980-09-06 | @ MIL | 137 | L 2-6 | 67-70 | 3 | 23,397 | Ken Clay | Mike Caldwell | Mike Caldwell | Ken Clay | | 657 | 625 | 32 |
| 1980-09-07 | @ MIL | 138 | W 7-2 | 68-70 | 3 | 18,201 | Doc Medich | Bob McClure | Doc Medich | Bob McClure | | 664 | 627 | 37 |
| 1980-09-08 | @ OAK | 139 | W 6-2 | 69-70 | 2 | 9,731 | John Butcher | Brian Kingman | John Butcher | Brian Kingman | | 670 | 629 | 41 |
| 1980-09-09 | @ OAK | 140 | L 3-6 | 69-71 | 3 | 2,443 | Ed Figueroa | Matt Keough | Matt Keough | Ed Figueroa | Jeff Jones | 673 | 635 | 38 |
| 1980-09-10 | @ OAK | 141 | L 1-3 | 69-72 | 3 | 3,598 | Jon Matlack | Mike Norris | Mike Norris | Jon Matlack | | 674 | 638 | 36 |
| 1980-09-12 | @ CAL | 142 | L 4-8 | 69-73 | 3 | 23,006 | Doc Medich | Jim Dorsey | Jim Dorsey | Doc Medich | Dave LaRoche | 678 | 646 | 32 |
| 1980-09-13 | @ CAL | 143 | L 1-10 | 69-74 | 3 | 26,060 | John Butcher | Alfredo Martinez | Alfredo Martinez | John Butcher | | 679 | 656 | 23 |
| 1980-09-14 | @ CAL | 144 | L 1-3 | 69-75 | 3 | 28,561 | Ken Clay | Frank Tanana | Frank Tanana | Ken Clay | Andy Hassler | 680 | 659 | 21 |
| 1980-09-15 | vs OAK | 145 | W 2-0 | 70-75 | 3 | 6,941 | Jon Matlack | Matt Keough | Jon Matlack | Matt Keough | John Henry Johnson | 682 | 659 | 23 |
| 1980-09-16 | vs OAK | 146 | L 2-4 | 70-76 | 3 | 7,295 | Doc Medich | Mike Norris | Mike Norris | Danny Darwin | | 684 | 663 | 21 |
| 1980-09-17 | vs OAK | 147 | L 4-6 | 70-77 | 3 | 7,255 | John Butcher | Rick Langford | Rick Langford | John Butcher | Bob Lacey | 688 | 669 | 19 |
| 1980-09-18 | vs OAK | 148 | W 10-6 | 71-77 | 3 | 7,560 | Ken Clay | Steve McCatty | Danny Darwin | Steve McCatty | John Henry Johnson | 698 | 675 | 23 |
| 1980-09-19 | vs CAL | 149 | L 2-6 | 71-78 | 3 | 9,024 | Jon Matlack | Frank Tanana | Frank Tanana | Jon Matlack | | 700 | 681 | 19 |
| 1980-09-20 | vs CAL | 150 | L 4-6 | 71-79 | 3 | 10,938 | Don Kainer | Jim Dorsey | Andy Hassler | Charlie Hough | | 704 | 687 | 17 |
| 1980-09-21 | vs CAL | 151 | L 2-9 | 71-80 | 3 | 6,794 | Doc Medich | Jim Barr | Jim Barr | Doc Medich | Don Aase | 706 | 696 | 10 |
| 1980-09-22 | @ MIN | 152 | L 0-1 | 71-81 | 3 | 2,377 | John Butcher | Jerry Koosman | Jerry Koosman | John Butcher | Doug Corbett | 706 | 697 | 9 |
| 1980-09-23 | @ MIN | 153 | L 2-8 | 71-82 | 3 | 2,427 | Ken Clay | Roger Erickson | Roger Erickson | Ken Clay | Pete Redfern | 708 | 705 | 3 |
| 1980-09-24 | @ MIN | 154 | L 5-9 | 71-83 | 4 | 2,863 | Jon Matlack | Albert Williams | Albert Williams | Jon Matlack | | 713 | 714 | -1 |
| 1980-09-25 | @ SEA | 155 | L 6-7 | 71-84 | 4 | 4,472 | Don Kainer | Rob Dressler | Dave Heaverlo | Danny Darwin | | 719 | 721 | -2 |
| 1980-09-26 | @ SEA | 156 | L 2-7 | 71-85 | 4 | 9,535 | Fergie Jenkins | Glenn Abbott | Glenn Abbott | Fergie Jenkins | | 721 | 728 | -7 |
| 1980-09-27 | @ SEA | 157 | W 7-3 | 72-85 | 4 | 12,496 | Doc Medich | Floyd Bannister | Doc Medich | Floyd Bannister | | 728 | 731 | -3 |
| 1980-09-28 | @ SEA | 158 | W 4-1 | 73-85 | 4 | 7,616 | John Butcher | Jim Beattie | John Butcher | Jim Beattie | Danny Darwin | 732 | 732 | 0 |
| 1980-10-02 | vs MIN | 159 | L 3-6 | 73-87 | 4 | 0 | Jon Matlack | Geoff Zahn | Geoff Zahn | Jon Matlack | | 735 | 738 | -3 |
| 1980-10-02 | vs MIN | 160 | L 1-4 | 73-87 | 4 | 8,022 | Fergie Jenkins | Albert Williams | Albert Williams | Fergie Jenkins | | 736 | 742 | -6 |
| 1980-10-03 | vs SEA | 161 | W 6-2 | 74-87 | 4 | 11,226 | Doc Medich | Glenn Abbott | Doc Medich | Glenn Abbott | | 742 | 744 | -2 |
| 1980-10-04 | vs SEA | 162 | W 11-6 | 75-87 | 4 | 9,241 | John Butcher | Jim Beattie | John Butcher | Jim Beattie | Jon Matlack | 753 | 750 | 3 |
| 1980-10-05 | vs SEA | 163 | W 3-2 | 76-87 | 4 | 7,384 | Don Kainer | Rick Anderson | Danny Darwin | Mike Parrott | | 756 | 752 | 4 |