| 1980-04-10 | vs BAL | 1 | L 3-5 | 0-1 | 4 | 35,539 | Steve Trout | Jim Palmer | Jim Palmer | Steve Trout | Tim Stoddard | 3 | 5 | -2 |
| 1980-04-11 | vs BAL | 2 | W 8-4 | 1-1 | 3 | 3,902 | Ken Kravec | Mike Flanagan | Ken Kravec | Mike Flanagan | Ed Farmer | 11 | 9 | 2 |
| 1980-04-12 | vs BAL | 3 | W 8-2 | 2-1 | 2 | 15,060 | Richard Dotson | Steve Stone | Richard Dotson | Steve Stone | | 19 | 11 | 8 |
| 1980-04-13 | vs BAL | 4 | W 5-2 | 3-1 | 1 | 16,279 | Ross Baumgarten | Dave Ford | Ross Baumgarten | Sammy Stewart | Ed Farmer | 24 | 13 | 11 |
| 1980-04-15 | vs NYA | 5 | W 4-3 | 4-1 | 1 | 6,614 | Steve Trout | Ron Guidry | Rich Wortham | Jim Kaat | | 28 | 16 | 12 |
| 1980-04-16 | vs NYA | 6 | L 0-6 | 4-2 | 2 | 9,680 | Ken Kravec | Tommy John | Tommy John | Ken Kravec | | 28 | 22 | 6 |
| 1980-04-17 | vs NYA | 7 | W 8-6 | 5-2 | 1 | 5,555 | Britt Burns | Mike Griffin | Britt Burns | Mike Griffin | Ed Farmer | 36 | 28 | 8 |
| 1980-04-18 | @ BAL | 8 | L 2-5 | 5-3 | 3 | 13,112 | Richard Dotson | Dave Ford | Dave Ford | Richard Dotson | | 38 | 33 | 5 |
| 1980-04-19 | @ BAL | 9 | W 5-4 | 6-3 | 2 | 25,239 | Ross Baumgarten | Jim Palmer | Ed Farmer | Tippy Martinez | | 43 | 37 | 6 |
| 1980-04-20 | @ BAL | 10 | W 9-6 | 7-3 | 2 | 21,617 | Steve Trout | Dennis Martinez | Rich Wortham | Sammy Stewart | Ed Farmer | 52 | 43 | 9 |
| 1980-04-21 | @ BOS | 11 | L 8-9 | 7-4 | 3 | 27,990 | Ken Kravec | Bruce Hurst | Skip Lockwood | Randy Scarbery | Dick Drago | 60 | 52 | 8 |
| 1980-04-22 | @ BOS | 12 | W 2-0 | 8-4 | 2 | 13,230 | Britt Burns | Mike Torrez | Britt Burns | Mike Torrez | Mike Proly | 62 | 52 | 10 |
| 1980-04-24 | @ BOS | 13 | W 9-3 | 9-4 | 2 | 12,385 | Richard Dotson | Bob Stanley | Richard Dotson | Bob Stanley | Ed Farmer | 71 | 55 | 16 |
| 1980-04-25 | @ NYA | 14 | W 6-0 | 10-4 | 1 | 17,076 | Steve Trout | Ed Figueroa | Steve Trout | Ed Figueroa | | 77 | 55 | 22 |
| 1980-04-26 | @ NYA | 15 | W 8-7 | 11-4 | 1 | 18,020 | Ken Kravec | Ron Guidry | Ed Farmer | Tom Underwood | Randy Scarbery | 85 | 62 | 23 |
| 1980-04-27 | @ NYA | 16 | L 0-1 | 11-5 | 1 | 20,431 | Britt Burns | Tommy John | Tommy John | Britt Burns | | 85 | 63 | 22 |
| 1980-04-29 | vs BOS | 17 | L 1-11 | 11-6 | 1 | 9,253 | Ross Baumgarten | Bob Stanley | Bob Stanley | Ross Baumgarten | | 86 | 74 | 12 |
| 1980-04-30 | vs BOS | 18 | W 2-1 | 12-6 | 1 | 10,626 | Richard Dotson | Dennis Eckersley | Richard Dotson | Dennis Eckersley | Ed Farmer | 88 | 75 | 13 |
| 1980-05-01 | vs BOS | 19 | L 3-4 | 12-7 | 1 | 8,155 | Steve Trout | Bruce Hurst | Bruce Hurst | Steve Trout | Tom Burgmeier | 91 | 79 | 12 |
| 1980-05-02 | vs MIL | 20 | L 0-8 | 12-8 | 2 | 22,276 | Ken Kravec | Mike Caldwell | Mike Caldwell | Ken Kravec | | 91 | 87 | 4 |
| 1980-05-03 | vs MIL | 21 | L 1-4 | 12-9 | 2 | 27,680 | Britt Burns | Moose Haas | Moose Haas | Britt Burns | Reggie Cleveland | 92 | 91 | 1 |
| 1980-05-04 | vs MIL | 22 | L 1-11 | 12-10 | 2 | 36,692 | Ross Baumgarten | Jim Slaton | Jim Slaton | Ross Baumgarten | | 93 | 102 | -9 |
| 1980-05-05 | vs MIL | 23 | W 11-7 | 13-10 | 2 | 27,871 | Richard Dotson | Lary Sorensen | Randy Scarbery | Dan Boitano | Ed Farmer | 104 | 109 | -5 |
| 1980-05-06 | vs KCA | 24 | W 2-0 | 14-10 | 2 | 7,938 | Rich Wortham | Larry Gura | Rich Wortham | Larry Gura | Ed Farmer | 106 | 109 | -3 |
| 1980-05-07 | vs KCA | 25 | L 5-12 | 14-11 | 2 | 7,584 | Ken Kravec | Rich Gale | Gary Christenson | Ken Kravec | | 111 | 121 | -10 |
| 1980-05-08 | vs KCA | 26 | W 8-2 | 15-11 | 2 | 7,410 | Britt Burns | Paul Splittorff | Britt Burns | Paul Splittorff | | 119 | 123 | -4 |
| 1980-05-09 | @ TEX | 27 | L 1-2 | 15-12 | 3 | 23,600 | Ross Baumgarten | Fergie Jenkins | Jim Kern | Mike Proly | | 120 | 125 | -5 |
| 1980-05-10 | @ TEX | 28 | W 10-6 | 16-12 | 2 | 24,327 | Richard Dotson | Gaylord Perry | Ed Farmer | Danny Darwin | | 130 | 131 | -1 |
| 1980-05-11 | @ TEX | 29 | L 1-5 | 16-13 | 3 | 17,849 | Rich Wortham | Doc Medich | Doc Medich | Rich Wortham | | 131 | 136 | -5 |
| 1980-05-13 | @ MIL | 30 | W 6-5 | 17-13 | 2 | 8,653 | Francisco Barrios | Bill Travers | Britt Burns | Reggie Cleveland | Ed Farmer | 137 | 141 | -4 |
| 1980-05-14 | @ MIL | 31 | L 1-5 | 17-14 | 3 | 11,232 | Ross Baumgarten | Moose Haas | Moose Haas | Mike Proly | Bob McClure | 138 | 146 | -8 |
| 1980-05-15 | @ MIL | 32 | W 6-4 | 18-14 | 3 | 22,733 | Richard Dotson | Lary Sorensen | Richard Dotson | Lary Sorensen | Randy Scarbery | 144 | 150 | -6 |
| 1980-05-16 | vs SEA | 33 | L 2-4 | 18-15 | 3 | 12,689 | Steve Trout | Jim Beattie | Jim Beattie | Steve Trout | Shane Rawley | 146 | 154 | -8 |
| 1980-05-17 | vs SEA | 34 | W 4-0 | 19-15 | 2 | 8,419 | Britt Burns | Rick Honeycutt | Britt Burns | Rick Honeycutt | | 150 | 154 | -4 |
| 1980-05-18 | vs SEA | 35 | W 6-5 | 20-15 | 1 | 24,625 | Francisco Barrios | Rob Dressler | Francisco Barrios | Rob Dressler | Ed Farmer | 156 | 159 | -3 |
| 1980-05-19 | vs MIN | 36 | W 1-0 | 21-15 | 1 | 9,272 | Ken Kravec | Jerry Koosman | Ken Kravec | Jerry Koosman | Ed Farmer | 157 | 159 | -2 |
| 1980-05-20 | vs MIN | 37 | W 4-2 | 22-15 | 1 | 12,864 | Richard Dotson | Darrell Jackson | Richard Dotson | Darrell Jackson | Ed Farmer | 161 | 161 | 0 |
| 1980-05-21 | vs MIN | 38 | L 2-3 | 22-16 | 1 | 33,967 | Steve Trout | Geoff Zahn | Geoff Zahn | Steve Trout | | 163 | 164 | -1 |
| 1980-05-23 | @ SEA | 39 | L 0-8 | 22-17 | 2 | 7,009 | Britt Burns | Rick Honeycutt | Rick Honeycutt | Britt Burns | Shane Rawley | 163 | 172 | -9 |
| 1980-05-24 | @ SEA | 40 | L 4-5 | 22-18 | 2 | 24,048 | Ken Kravec | Glenn Abbott | Glenn Abbott | Ken Kravec | Dave Roberts | 167 | 177 | -10 |
| 1980-05-25 | @ SEA | 41 | L 3-8 | 22-19 | 2 | 8,071 | Richard Dotson | Floyd Bannister | Floyd Bannister | Randy Scarbery | | 170 | 185 | -15 |
| 1980-05-26 | @ MIN | 42 | W 6-3 | 23-19 | 2 | 5,436 | Steve Trout | Geoff Zahn | Steve Trout | Geoff Zahn | Ed Farmer | 176 | 188 | -12 |
| 1980-05-27 | @ MIN | 43 | W 2-0 | 24-19 | 2 | 4,362 | Britt Burns | Darrell Jackson | Britt Burns | Darrell Jackson | Mike Proly | 178 | 188 | -10 |
| 1980-05-28 | @ MIN | 44 | L 4-6 | 24-20 | 2 | 4,256 | Ken Kravec | Pete Redfern | Mike Marshall | Mike Proly | | 182 | 194 | -12 |
| 1980-05-29 | @ MIN | 45 | L 2-5 | 24-21 | 2 | 5,204 | Richard Dotson | Jerry Koosman | Jerry Koosman | Richard Dotson | | 184 | 199 | -15 |
| 1980-05-30 | @ KCA | 46 | L 2-9 | 24-22 | 3 | 26,550 | Rich Wortham | Larry Gura | Larry Gura | Rich Wortham | | 186 | 208 | -22 |
| 1980-05-31 | @ KCA | 47 | L 4-6 | 24-23 | 3 | 29,050 | Steve Trout | Renie Martin | Renie Martin | Steve Trout | Dan Quisenberry | 190 | 214 | -24 |
| 1980-06-01 | @ KCA | 48 | W 6-1 | 25-23 | 3 | 33,428 | Britt Burns | Dennis Leonard | Britt Burns | Dennis Leonard | | 196 | 215 | -19 |
| 1980-06-02 | vs TEX | 49 | W 1-1 | 26-23 | 2 | 10,586 | Ross Baumgarten | Jon Matlack | | | | 197 | 216 | -19 |
| 1980-06-03 | vs TEX | 50 | W 5-4 | 27-23 | 2 | 12,232 | Ken Kravec | Gaylord Perry | Ed Farmer | Jim Kern | Rich Wortham | 202 | 220 | -18 |
| 1980-06-04 | vs TEX | 51 | L 3-4 | 28-24 | 2 | 0 | Francisco Barrios | Doc Medich | Doc Medich | Francisco Barrios | Sparky Lyle | 205 | 224 | -19 |
| 1980-06-04 | vs TEX | 52 | W 5-1 | 28-24 | 2 | 16,000 | Richard Dotson | Dave Rajsich | Richard Dotson | Dave Rajsich | | 210 | 225 | -15 |
| 1980-06-06 | vs CLE | 53 | W 8-7 | 29-24 | 2 | 20,231 | Steve Trout | Rick Waits | Ed Farmer | Sid Monge | | 218 | 232 | -14 |
| 1980-06-08 | vs CLE | 54 | L 2-7 | 29-25 | 2 | 31,593 | Britt Burns | John Denny | John Denny | Britt Burns | Mike Stanton | 220 | 239 | -19 |
| 1980-06-10 | vs TOR | 55 | L 0-1 | 29-26 | 2 | 18,225 | Ross Baumgarten | Jim Clancy | Jim Clancy | Ross Baumgarten | | 220 | 240 | -20 |
| 1980-06-11 | vs TOR | 56 | W 7-4 | 30-26 | 2 | 17,537 | Ken Kravec | Paul Mirabella | Ken Kravec | Paul Mirabella | Ed Farmer | 227 | 244 | -17 |
| 1980-06-13 | @ DET | 57 | L 4-8 | 30-27 | 2 | 33,767 | Steve Trout | Jack Morris | Jack Morris | Steve Trout | | 231 | 252 | -21 |
| 1980-06-14 | @ DET | 58 | L 0-3 | 30-28 | 2 | 31,008 | Britt Burns | Dan Petry | Dan Petry | Britt Burns | | 231 | 255 | -24 |
| 1980-06-16 | @ CLE | 59 | L 3-5 | 30-29 | 2 | 11,184 | Ross Baumgarten | Wayne Garland | Wayne Garland | Ed Farmer | | 234 | 260 | -26 |
| 1980-06-17 | @ CLE | 60 | W 5-3 | 31-29 | 2 | 9,614 | Ken Kravec | Rick Waits | LaMarr Hoyt | Victor Cruz | | 239 | 263 | -24 |
| 1980-06-18 | @ TOR | 61 | L 4-5 | 31-31 | 2 | 0 | Steve Trout | Dave Stieb | Dave Stieb | Steve Trout | | 243 | 268 | -25 |
| 1980-06-18 | @ TOR | 62 | L 1-3 | 31-31 | 2 | 21,443 | Richard Dotson | Jack Kucek | Jack Kucek | Richard Dotson | Joey McLaughlin | 244 | 271 | -27 |
| 1980-06-20 | vs DET | 63 | L 3-5 | 31-32 | 2 | 27,241 | Britt Burns | Dan Petry | Aurelio Lopez | Ed Farmer | | 247 | 276 | -29 |
| 1980-06-21 | vs DET | 64 | L 1-4 | 31-33 | 2 | 23,990 | Ross Baumgarten | Milt Wilcox | Milt Wilcox | Ross Baumgarten | | 248 | 280 | -32 |
| 1980-06-22 | vs DET | 65 | L 1-7 | 31-35 | 2 | 0 | Ken Kravec | Dave Rozema | Dave Rozema | Ken Kravec | | 249 | 287 | -38 |
| 1980-06-22 | vs DET | 66 | L 4-6 | 31-35 | 2 | 27,100 | Rich Wortham | Jack Morris | Jack Morris | Rich Wortham | Aurelio Lopez | 253 | 293 | -40 |
| 1980-06-24 | @ CAL | 67 | W 2-1 | 32-35 | 2 | 25,142 | Britt Burns | Don Aase | Britt Burns | Don Aase | Ed Farmer | 255 | 294 | -39 |
| 1980-06-25 | @ CAL | 68 | W 5-2 | 33-35 | 2 | 25,372 | Richard Dotson | Dave Frost | Richard Dotson | Dave Lemanczyk | Ed Farmer | 260 | 296 | -36 |
| 1980-06-26 | @ CAL | 69 | W 5-2 | 34-35 | 2 | 24,755 | Steve Trout | Frank Tanana | Steve Trout | Frank Tanana | Mike Proly | 265 | 298 | -33 |
| 1980-06-27 | @ OAK | 70 | L 1-3 | 34-36 | 2 | 8,482 | Ross Baumgarten | Mike Norris | Mike Norris | Ross Baumgarten | | 266 | 301 | -35 |
| 1980-06-28 | @ OAK | 71 | W 3-0 | 35-36 | 2 | 5,204 | Rich Wortham | Matt Keough | Rich Wortham | Matt Keough | Ed Farmer | 269 | 301 | -32 |
| 1980-06-29 | @ OAK | 72 | W 3-0 | 36-36 | 2 | 7,369 | Britt Burns | Brian Kingman | Britt Burns | Brian Kingman | Mike Proly | 272 | 301 | -29 |
| 1980-06-30 | vs CAL | 73 | L 6-10 | 36-37 | 2 | 17,678 | Richard Dotson | Chris Knapp | Mark Clear | Ed Farmer | | 278 | 311 | -33 |
| 1980-07-01 | vs CAL | 74 | L 2-5 | 36-38 | 2 | 17,116 | Steve Trout | Ed Halicki | Ed Halicki | Steve Trout | Mark Clear | 280 | 316 | -36 |
| 1980-07-02 | vs CAL | 75 | W 1-0 | 37-38 | 2 | 11,653 | Ross Baumgarten | Frank Tanana | Ross Baumgarten | Frank Tanana | | 281 | 316 | -35 |
| 1980-07-03 | vs CAL | 76 | L 3-7 | 37-39 | 2 | 32,506 | Rich Wortham | Dave Lemanczyk | Dave Lemanczyk | Rich Wortham | Mark Clear | 284 | 323 | -39 |
| 1980-07-04 | vs OAK | 77 | L 0-2 | 37-40 | 2 | 11,428 | Britt Burns | Brian Kingman | Brian Kingman | Britt Burns | | 284 | 325 | -41 |
| 1980-07-05 | vs OAK | 78 | L 0-5 | 37-41 | 2 | 20,559 | Richard Dotson | Rick Langford | Rick Langford | Richard Dotson | | 284 | 330 | -46 |
| 1980-07-06 | vs OAK | 79 | W 2-0 | 39-41 | 2 | 0 | Steve Trout | Mike Norris | Steve Trout | Mike Norris | | 286 | 330 | -44 |
| 1980-07-06 | vs OAK | 80 | W 5-4 | 39-41 | 2 | 16,436 | Ken Kravec | Steve McCatty | Ed Farmer | Bob Lacey | | 291 | 334 | -43 |
| 1980-07-10 | vs BAL | 81 | L 2-9 | 39-42 | 2 | 21,839 | Britt Burns | Scott McGregor | Scott McGregor | Britt Burns | | 293 | 343 | -50 |
| 1980-07-11 | vs BAL | 82 | W 5-4 | 40-42 | 2 | 28,457 | Richard Dotson | Jim Palmer | Mike Proly | Jim Palmer | Ed Farmer | 298 | 347 | -49 |
| 1980-07-12 | vs NYA | 83 | L 0-8 | 40-43 | 2 | 34,308 | Ross Baumgarten | Tommy John | Tommy John | Ross Baumgarten | | 298 | 355 | -57 |
| 1980-07-13 | vs NYA | 84 | L 1-3 | 40-44 | 2 | 28,984 | Steve Trout | Rudy May | Rudy May | Steve Trout | | 299 | 358 | -59 |
| 1980-07-14 | vs NYA | 85 | L 6-7 | 40-45 | 2 | 25,185 | Rich Wortham | Ed Figueroa | Ron Davis | Ed Farmer | Rich Gossage | 305 | 365 | -60 |
| 1980-07-15 | @ TEX | 86 | W 2-1 | 41-45 | 2 | 13,777 | Britt Burns | Fergie Jenkins | Britt Burns | Fergie Jenkins | | 307 | 366 | -59 |
| 1980-07-16 | @ TEX | 87 | L 3-11 | 41-46 | 2 | 11,256 | Richard Dotson | Jon Matlack | Jon Matlack | Richard Dotson | Sparky Lyle | 310 | 377 | -67 |
| 1980-07-17 | @ TEX | 88 | L 2-3 | 41-47 | 3 | 13,489 | Ross Baumgarten | Gaylord Perry | Danny Darwin | Mike Proly | | 312 | 380 | -68 |
| 1980-07-18 | @ MIL | 89 | L 1-5 | 41-48 | 4 | 46,951 | Steve Trout | Moose Haas | Moose Haas | Steve Trout | | 313 | 385 | -72 |
| 1980-07-19 | @ MIL | 90 | W 10-7 | 42-48 | 4 | 49,322 | Rich Wortham | Paul Mitchell | LaMarr Hoyt | Bob McClure | Ed Farmer | 323 | 392 | -69 |
| 1980-07-20 | @ MIL | 91 | L 6-7 | 42-49 | 5 | 44,799 | Richard Dotson | Reggie Cleveland | Jerry Augustine | Mike Proly | Bob McClure | 329 | 399 | -70 |
| 1980-07-21 | @ KCA | 92 | L 1-2 | 42-50 | 5 | 37,054 | Britt Burns | Dennis Leonard | Dennis Leonard | Britt Burns | Dan Quisenberry | 330 | 401 | -71 |
| 1980-07-22 | @ KCA | 93 | W 6-1 | 43-50 | 4 | 28,891 | Steve Trout | Steve Busby | Steve Trout | Steve Busby | | 336 | 402 | -66 |
| 1980-07-23 | @ KCA | 94 | L 2-9 | 43-51 | 4 | 25,105 | Ross Baumgarten | Larry Gura | Larry Gura | Ross Baumgarten | | 338 | 411 | -73 |
| 1980-07-24 | @ KCA | 95 | L 4-12 | 43-52 | 5 | 29,052 | Rich Wortham | Paul Splittorff | Paul Splittorff | Rich Wortham | | 342 | 423 | -81 |
| 1980-07-25 | vs TEX | 96 | L 4-6 | 43-53 | 5 | 22,491 | Richard Dotson | Steve Comer | Jim Kern | Ed Farmer | | 346 | 429 | -83 |
| 1980-07-26 | vs TEX | 97 | W 4-3 | 45-53 | 4 | 0 | LaMarr Hoyt | Fergie Jenkins | LaMarr Hoyt | Fergie Jenkins | | 350 | 432 | -82 |
| 1980-07-26 | vs TEX | 98 | W 1-1 | 45-53 | 4 | 21,503 | Britt Burns | Gaylord Perry | | | | 351 | 433 | -82 |
| 1980-07-27 | vs TEX | 99 | W 3-2 | 46-54 | 4 | 0 | Steve Trout | Doc Medich | Steve Trout | Doc Medich | Mike Proly | 354 | 435 | -81 |
| 1980-07-27 | vs TEX | 100 | L 3-4 | 46-54 | 4 | 12,364 | Rich Wortham | Jon Matlack | Charlie Hough | Mike Proly | | 357 | 439 | -82 |
| 1980-07-29 | vs MIL | 101 | L 1-7 | 46-55 | 5 | 31,832 | Richard Dotson | Moose Haas | Moose Haas | Richard Dotson | | 358 | 446 | -88 |
| 1980-07-30 | vs MIL | 102 | W 6-5 | 47-55 | 5 | 13,344 | LaMarr Hoyt | Reggie Cleveland | LaMarr Hoyt | Lary Sorensen | Mike Proly | 364 | 451 | -87 |
| 1980-08-01 | vs KCA | 103 | L 3-4 | 47-56 | 5 | 23,316 | Britt Burns | Larry Gura | Larry Gura | Britt Burns | Dan Quisenberry | 367 | 455 | -88 |
| 1980-08-02 | vs KCA | 104 | L 2-8 | 47-57 | 5 | 14,905 | Steve Trout | Rich Gale | Rich Gale | Steve Trout | Marty Pattin | 369 | 463 | -94 |
| 1980-08-03 | vs KCA | 105 | W 5-3 | 48-57 | 4 | 14,329 | Richard Dotson | Paul Splittorff | Richard Dotson | Paul Splittorff | | 374 | 466 | -92 |
| 1980-08-05 | @ BAL | 106 | L 2-8 | 48-58 | 4 | 14,303 | LaMarr Hoyt | Steve Stone | Steve Stone | LaMarr Hoyt | | 376 | 474 | -98 |
| 1980-08-06 | @ BAL | 107 | L 1-4 | 48-59 | 4 | 21,538 | Britt Burns | Mike Flanagan | Mike Flanagan | Britt Burns | Tim Stoddard | 377 | 478 | -101 |
| 1980-08-07 | @ BAL | 108 | L 1-2 | 48-60 | 4 | 21,750 | Steve Trout | Scott McGregor | Scott McGregor | Steve Trout | | 378 | 480 | -102 |
| 1980-08-08 | @ BOS | 109 | L 1-4 | 48-61 | 4 | 29,326 | Richard Dotson | Skip Lockwood | Bill Campbell | Richard Dotson | Bob Stanley | 379 | 484 | -105 |
| 1980-08-09 | @ BOS | 110 | W 5-4 | 49-61 | 4 | 32,719 | Mike Proly | Steve Renko | Mike Proly | Steve Renko | Ed Farmer | 384 | 488 | -104 |
| 1980-08-10 | @ BOS | 111 | L 3-4 | 49-62 | 4 | 30,124 | LaMarr Hoyt | Dennis Eckersley | Dennis Eckersley | LaMarr Hoyt | Bob Stanley | 387 | 492 | -105 |
| 1980-08-11 | @ NYA | 112 | L 1-3 | 49-63 | 4 | 28,292 | Britt Burns | Rudy May | Rudy May | Britt Burns | | 388 | 495 | -107 |
| 1980-08-12 | @ NYA | 113 | L 4-8 | 49-64 | 5 | 27,883 | Steve Trout | Luis Tiant | Doug Bird | Ed Farmer | | 392 | 503 | -111 |
| 1980-08-13 | @ NYA | 114 | W 4-1 | 50-64 | 4 | 33,775 | Richard Dotson | Ron Guidry | Richard Dotson | Ron Guidry | | 396 | 504 | -108 |
| 1980-08-15 | vs BOS | 115 | L 5-8 | 50-65 | 4 | 22,521 | Mike Proly | Dennis Eckersley | Dennis Eckersley | Mike Proly | Bob Stanley | 401 | 512 | -111 |
| 1980-08-18 | vs CLE | 116 | L 2-4 | 51-66 | 5 | 0 | Britt Burns | Len Barker | Len Barker | Britt Burns | | 403 | 516 | -113 |
| 1980-08-18 | vs CLE | 117 | W 7-2 | 51-66 | 5 | 16,270 | Steve Trout | Wayne Garland | Steve Trout | Wayne Garland | | 410 | 518 | -108 |
| 1980-08-19 | vs CLE | 118 | L 5-8 | 51-67 | 5 | 10,001 | Richard Dotson | Ross Grimsley | Ross Grimsley | Richard Dotson | Sid Monge | 415 | 526 | -111 |
| 1980-08-20 | vs CLE | 119 | L 0-3 | 51-68 | 5 | 8,696 | Ken Kravec | Dan Spillner | Dan Spillner | Ken Kravec | | 415 | 529 | -114 |
| 1980-08-21 | vs TOR | 120 | W 5-3 | 52-68 | 5 | 15,303 | LaMarr Hoyt | Jesse Jefferson | LaMarr Hoyt | Jesse Jefferson | Ed Farmer | 420 | 532 | -112 |
| 1980-08-22 | vs TOR | 121 | W 2-0 | 53-68 | 5 | 15,033 | Britt Burns | Jim Clancy | Britt Burns | Jim Clancy | Ed Farmer | 422 | 532 | -110 |
| 1980-08-23 | vs TOR | 122 | W 5-1 | 54-68 | 4 | 10,768 | Richard Dotson | Jack Kucek | Richard Dotson | Jack Kucek | | 427 | 533 | -106 |
| 1980-08-24 | vs TOR | 123 | L 3-7 | 54-69 | 4 | 17,156 | Ross Baumgarten | Dave Stieb | Dave Stieb | Ross Baumgarten | Mike Barlow | 430 | 540 | -110 |
| 1980-08-26 | vs DET | 124 | L 4-5 | 54-70 | 4 | 10,061 | LaMarr Hoyt | Jerry Ujdur | Aurelio Lopez | Rich Wortham | Pat Underwood | 434 | 545 | -111 |
| 1980-08-27 | vs DET | 125 | W 3-2 | 55-70 | 4 | 12,582 | Britt Burns | Jack Morris | Mike Proly | Dave Rozema | | 437 | 547 | -110 |
| 1980-08-29 | @ CLE | 126 | L 5-6 | 55-71 | 5 | 9,044 | Richard Dotson | Wayne Garland | Sid Monge | Ed Farmer | Victor Cruz | 442 | 553 | -111 |
| 1980-08-30 | @ CLE | 127 | L 2-6 | 55-72 | 5 | 11,787 | Ross Baumgarten | Dan Spillner | Dan Spillner | Ross Baumgarten | Victor Cruz | 444 | 559 | -115 |
| 1980-08-31 | @ CLE | 128 | W 10-8 | 57-72 | 4 | 0 | LaMarr Hoyt | Rick Waits | LaMarr Hoyt | Victor Cruz | Ed Farmer | 454 | 567 | -113 |
| 1980-08-31 | @ CLE | 129 | W 8-7 | 57-72 | 4 | 19,131 | Steve Trout | Ross Grimsley | Steve Trout | Ross Grimsley | Ed Farmer | 462 | 574 | -112 |
| 1980-09-01 | @ DET | 130 | W 11-3 | 58-72 | 4 | 11,412 | Britt Burns | Jack Morris | Britt Burns | Jack Morris | | 473 | 577 | -104 |
| 1980-09-02 | @ DET | 131 | L 2-11 | 58-74 | 4 | 0 | Mike Proly | Mark Fidrych | Mark Fidrych | Mike Proly | | 475 | 588 | -113 |
| 1980-09-02 | @ DET | 132 | L 1-6 | 58-74 | 4 | 13,651 | Richard Dotson | Milt Wilcox | Milt Wilcox | Richard Dotson | | 476 | 594 | -118 |
| 1980-09-03 | @ DET | 133 | L 4-5 | 58-75 | 4 | 10,395 | Guy Hoffman | Dave Rozema | Aurelio Lopez | Rich Wortham | | 480 | 599 | -119 |
| 1980-09-04 | @ TOR | 134 | L 2-3 | 58-76 | 4 | 12,365 | Ross Baumgarten | Jackson Todd | Jackson Todd | Ed Farmer | | 482 | 602 | -120 |
| 1980-09-05 | @ TOR | 135 | W 3-0 | 59-76 | 4 | 14,091 | LaMarr Hoyt | Jim Clancy | LaMarr Hoyt | Jim Clancy | | 485 | 602 | -117 |
| 1980-09-07 | @ TOR | 136 | L 1-3 | 59-78 | 5 | 0 | Steve Trout | Joey McLaughlin | Joey McLaughlin | Steve Trout | Mike Barlow | 486 | 605 | -119 |
| 1980-09-07 | @ TOR | 137 | L 6-7 | 59-78 | 5 | 17,457 | Britt Burns | Luis Leal | Ken Schrom | Mike Proly | Mike Barlow | 492 | 612 | -120 |
| 1980-09-08 | vs SEA | 138 | W 3-2 | 60-78 | 4 | 5,184 | Richard Dotson | Rob Dressler | Ed Farmer | Dave Heaverlo | | 495 | 614 | -119 |
| 1980-09-09 | vs SEA | 139 | L 1-4 | 60-79 | 5 | 5,247 | Ross Baumgarten | Rick Honeycutt | Rick Honeycutt | Ross Baumgarten | Byron McLaughlin | 496 | 618 | -122 |
| 1980-09-10 | vs SEA | 140 | W 4-3 | 61-79 | 4 | 3,028 | LaMarr Hoyt | Glenn Abbott | LaMarr Hoyt | Manny Sarmiento | Ed Farmer | 500 | 621 | -121 |
| 1980-09-12 | vs MIN | 141 | W 5-3 | 62-79 | 4 | 10,161 | Britt Burns | Jerry Koosman | Britt Burns | Jerry Koosman | Ed Farmer | 505 | 624 | -119 |
| 1980-09-13 | vs MIN | 142 | L 5-6 | 62-80 | 4 | 7,988 | Steve Trout | Geoff Zahn | Geoff Zahn | Steve Trout | Doug Corbett | 510 | 630 | -120 |
| 1980-09-14 | vs MIN | 143 | L 2-3 | 62-81 | 5 | 11,288 | Ross Baumgarten | Albert Williams | Fernando Arroyo | Ross Baumgarten | Doug Corbett | 512 | 633 | -121 |
| 1980-09-15 | @ SEA | 144 | L 1-12 | 62-82 | 5 | 4,141 | LaMarr Hoyt | Rob Dressler | Rob Dressler | LaMarr Hoyt | | 513 | 645 | -132 |
| 1980-09-16 | @ SEA | 145 | W 2-1 | 63-82 | 5 | 5,149 | Richard Dotson | Glenn Abbott | Richard Dotson | Glenn Abbott | Ed Farmer | 515 | 646 | -131 |
| 1980-09-17 | @ SEA | 146 | L 0-4 | 63-83 | 5 | 5,435 | Britt Burns | Floyd Bannister | Floyd Bannister | Britt Burns | Mike Parrott | 515 | 650 | -135 |
| 1980-09-18 | @ SEA | 147 | W 5-4 | 64-83 | 5 | 4,293 | Steve Trout | Jim Beattie | Mike Proly | Shane Rawley | Guy Hoffman | 520 | 654 | -134 |
| 1980-09-19 | @ MIN | 148 | L 3-6 | 64-84 | 5 | 2,911 | Ross Baumgarten | Albert Williams | Albert Williams | Ed Farmer | Doug Corbett | 523 | 660 | -137 |
| 1980-09-21 | @ MIN | 149 | L 4-5 | 64-86 | 5 | 0 | LaMarr Hoyt | Geoff Zahn | John Verhoeven | Dewey Robinson | | 527 | 665 | -138 |
| 1980-09-21 | @ MIN | 150 | L 4-6 | 64-86 | 5 | 4,066 | Richard Dotson | Fernando Arroyo | Fernando Arroyo | Richard Dotson | Pete Redfern | 531 | 671 | -140 |
| 1980-09-23 | @ OAK | 151 | L 4-6 | 64-87 | 6 | 3,069 | Britt Burns | Rick Langford | Rick Langford | Mike Proly | | 535 | 677 | -142 |
| 1980-09-24 | @ OAK | 152 | L 1-7 | 64-88 | 6 | 2,836 | Steve Trout | Steve McCatty | Steve McCatty | Steve Trout | | 536 | 684 | -148 |
| 1980-09-25 | @ OAK | 153 | W 6-4 | 65-88 | 5 | 3,180 | Ross Baumgarten | Matt Keough | Mike Proly | Brian Kingman | Ed Farmer | 542 | 688 | -146 |
| 1980-09-26 | @ CAL | 154 | W 5-4 | 66-88 | 5 | 22,578 | LaMarr Hoyt | Jim Barr | Dewey Robinson | Jim Barr | Ed Farmer | 547 | 692 | -145 |
| 1980-09-27 | @ CAL | 155 | W 6-3 | 67-88 | 5 | 20,398 | Richard Dotson | Ralph Botting | Richard Dotson | Ralph Botting | | 553 | 695 | -142 |
| 1980-09-28 | @ CAL | 156 | W 8-1 | 68-88 | 5 | 29,012 | Britt Burns | Alfredo Martinez | Britt Burns | Alfredo Martinez | | 561 | 696 | -135 |
| 1980-09-30 | vs OAK | 157 | L 1-5 | 68-89 | 5 | 18,903 | Steve Trout | Brian Kingman | Brian Kingman | Steve Trout | Bob Lacey | 562 | 701 | -139 |
| 1980-10-01 | vs OAK | 158 | L 3-11 | 68-90 | 5 | 2,258 | Ross Baumgarten | Mike Norris | Mike Norris | Ross Baumgarten | | 565 | 712 | -147 |
| 1980-10-02 | vs OAK | 159 | W 9-4 | 69-90 | 5 | 2,202 | Richard Dotson | Rick Langford | Guy Hoffman | Rick Langford | | 574 | 716 | -142 |
| 1980-10-03 | vs CAL | 160 | W 4-1 | 70-90 | 5 | 6,722 | Britt Burns | Alfredo Martinez | Britt Burns | Alfredo Martinez | Mike Proly | 578 | 717 | -139 |
| 1980-10-04 | vs CAL | 161 | W 4-2 | 71-90 | 5 | 7,788 | LaMarr Hoyt | Frank Tanana | LaMarr Hoyt | Frank Tanana | Ed Farmer | 582 | 719 | -137 |
| 1980-10-05 | vs CAL | 162 | W 5-3 | 72-90 | 5 | 8,795 | Steve Trout | Ralph Botting | Steve Trout | Ralph Botting | Mike Proly | 587 | 722 | -135 |