| 1981-04-11 | @ CLE | 1 | W 5-3 | - | | 71,067 | Mike Caldwell | Bert Blyleven | Mike Caldwell | Bert Blyleven | Rollie Fingers | 5 | 3 | 2 |
| 1981-04-12 | @ CLE | 2 | W 6-1 | - | | 13,094 | Jim Slaton | John Denny | Jim Slaton | John Denny | Jamie Easterly | 11 | 4 | 7 |
| 1981-04-14 | @ CHA | 3 | L 3-9 | - | | 51,560 | Pete Vuckovich | Ross Baumgarten | Ross Baumgarten | Pete Vuckovich | | 14 | 13 | 1 |
| 1981-04-15 | @ CHA | 4 | L 4-5 | - | | 13,212 | Moose Haas | Britt Burns | LaMarr Hoyt | Rollie Fingers | | 18 | 18 | 0 |
| 1981-04-16 | vs CLE | 5 | L 0-1 | - | | 54,296 | Mike Caldwell | Wayne Garland | Wayne Garland | Mike Caldwell | | 18 | 19 | -1 |
| 1981-04-18 | vs CLE | 6 | L 0-5 | - | | 18,250 | Jim Slaton | Bert Blyleven | Bert Blyleven | Jim Slaton | | 18 | 24 | -6 |
| 1981-04-20 | @ TOR | 7 | W 5-4 | - | | 12,298 | Pete Vuckovich | Jackson Todd | Randy Lerch | Mike Willis | | 23 | 28 | -5 |
| 1981-04-21 | @ TOR | 8 | W 6-2 | - | | 11,083 | Moose Haas | Dave Stieb | Moose Haas | Dave Stieb | | 29 | 30 | -1 |
| 1981-04-22 | @ TOR | 9 | W 8-1 | - | | 11,792 | Mike Caldwell | Luis Leal | Mike Caldwell | Luis Leal | | 37 | 31 | 6 |
| 1981-04-24 | vs KCA | 10 | W 6-1 | - | | 12,397 | Jim Slaton | Rich Gale | Jim Slaton | Rich Gale | | 43 | 32 | 11 |
| 1981-04-25 | vs KCA | 11 | L 2-4 | - | | 18,858 | Pete Vuckovich | Larry Gura | Larry Gura | Pete Vuckovich | | 45 | 36 | 9 |
| 1981-04-26 | vs KCA | 12 | W 11-1 | - | | 24,398 | Randy Lerch | Dennis Leonard | Randy Lerch | Dennis Leonard | | 56 | 37 | 19 |
| 1981-04-27 | vs TOR | 13 | W 4-3 | - | | 6,692 | Moose Haas | Luis Leal | Reggie Cleveland | Jerry Garvin | | 60 | 40 | 20 |
| 1981-04-28 | vs TOR | 14 | L 2-6 | - | | 6,433 | Mike Caldwell | Mark Bomback | Mark Bomback | Mike Caldwell | | 62 | 46 | 16 |
| 1981-04-29 | vs TOR | 15 | L 0-5 | - | | 7,320 | Jim Slaton | Jerry Garvin | Luis Leal | Jamie Easterly | | 62 | 51 | 11 |
| 1981-04-30 | @ CAL | 16 | W 12-1 | - | | 23,428 | Jerry Augustine | Jesse Jefferson | Jerry Augustine | Jesse Jefferson | | 74 | 52 | 22 |
| 1981-05-01 | @ CAL | 17 | L 4-8 | - | | 26,031 | Randy Lerch | Mike Witt | Mike Witt | Randy Lerch | | 78 | 60 | 18 |
| 1981-05-02 | @ CAL | 18 | W 8-5 | - | | 32,348 | Moose Haas | Ken Forsch | Moose Haas | Ken Forsch | Jamie Easterly | 86 | 65 | 21 |
| 1981-05-03 | @ CAL | 19 | W 4-3 | - | | 27,114 | Mike Caldwell | Steve Renko | Mike Caldwell | Steve Renko | Rollie Fingers | 90 | 68 | 22 |
| 1981-05-04 | @ SEA | 20 | W 9-5 | - | | 5,075 | Jim Slaton | Brian Allard | Jamie Easterly | Brian Allard | Rollie Fingers | 99 | 73 | 26 |
| 1981-05-05 | @ SEA | 21 | W 4-1 | - | | 5,044 | Pete Vuckovich | Jerry Gleaton | Pete Vuckovich | Jerry Gleaton | Rollie Fingers | 103 | 74 | 29 |
| 1981-05-06 | @ SEA | 22 | L 1-12 | - | | 4,828 | Randy Lerch | Mike Parrott | Mike Parrott | Randy Lerch | | 104 | 86 | 18 |
| 1981-05-07 | @ SEA | 23 | L 1-4 | - | | 5,855 | Moose Haas | Floyd Bannister | Floyd Bannister | Moose Haas | | 105 | 90 | 15 |
| 1981-05-08 | @ OAK | 24 | L 0-2 | - | | 28,708 | Mike Caldwell | Steve McCatty | Steve McCatty | Mike Caldwell | | 105 | 92 | 13 |
| 1981-05-09 | @ OAK | 25 | L 5-6 | - | | 27,308 | Jim Slaton | Brian Kingman | Bob Owchinko | Randy Lerch | | 110 | 98 | 12 |
| 1981-05-10 | @ OAK | 26 | W 13-5 | - | | 28,581 | Pete Vuckovich | Mike Norris | Pete Vuckovich | Mike Norris | Jerry Augustine | 123 | 103 | 20 |
| 1981-05-12 | vs CAL | 27 | L 0-4 | - | | 8,420 | Moose Haas | Ken Forsch | Ken Forsch | Moose Haas | | 123 | 107 | 16 |
| 1981-05-13 | vs CAL | 28 | L 3-6 | - | | 8,851 | Mike Caldwell | Steve Renko | Steve Renko | Mike Caldwell | Andy Hassler | 126 | 113 | 13 |
| 1981-05-14 | vs CAL | 29 | L 1-9 | - | | 10,969 | Jim Slaton | Geoff Zahn | Geoff Zahn | Jim Slaton | | 127 | 122 | 5 |
| 1981-05-15 | vs OAK | 30 | W 3-0 | - | | 29,667 | Pete Vuckovich | Steve McCatty | Pete Vuckovich | Steve McCatty | Rollie Fingers | 130 | 122 | 8 |
| 1981-05-16 | vs OAK | 31 | W 6-5 | - | | 33,937 | Randy Lerch | Brian Kingman | Reggie Cleveland | Bob Owchinko | Rollie Fingers | 136 | 127 | 9 |
| 1981-05-17 | vs OAK | 32 | W 6-2 | - | | 33,142 | Moose Haas | Rick Langford | Moose Haas | Rick Langford | | 142 | 129 | 13 |
| 1981-05-19 | vs MIN | 33 | W 4-3 | - | | 8,979 | Mike Caldwell | Fernando Arroyo | Mike Caldwell | Fernando Arroyo | Rollie Fingers | 146 | 132 | 14 |
| 1981-05-20 | vs MIN | 34 | W 6-1 | - | | 10,463 | Jim Slaton | Albert Williams | Jim Slaton | Albert Williams | Rollie Fingers | 152 | 133 | 19 |
| 1981-05-21 | vs MIN | 35 | W 8-2 | - | | 16,120 | Pete Vuckovich | Pete Redfern | Pete Vuckovich | Pete Redfern | | 160 | 135 | 25 |
| 1981-05-22 | vs BOS | 36 | L 3-7 | - | | 23,007 | Moose Haas | John Tudor | John Tudor | Moose Haas | | 163 | 142 | 21 |
| 1981-05-23 | vs BOS | 37 | L 1-8 | - | | 35,254 | Randy Lerch | Mike Torrez | Mike Torrez | Randy Lerch | Mark Clear | 164 | 150 | 14 |
| 1981-05-24 | vs BOS | 38 | W 2-1 | - | | 0 | Mike Caldwell | Frank Tanana | Jamie Easterly | Bob Stanley | | 166 | 151 | 15 |
| 1981-05-24 | vs BOS | 39 | W 10-7 | - | | 34,992 | Jim Slaton | Chuck Rainey | Moose Haas | Bob Stanley | | 176 | 158 | 18 |
| 1981-05-25 | vs DET | 40 | L 3-12 | - | | 25,072 | Jerry Augustine | Jack Morris | Jack Morris | Jerry Augustine | | 179 | 170 | 9 |
| 1981-05-26 | vs DET | 41 | W 7-3 | - | | 9,518 | Pete Vuckovich | Milt Wilcox | Pete Vuckovich | Milt Wilcox | | 186 | 173 | 13 |
| 1981-05-27 | vs DET | 42 | W 5-1 | - | | 13,237 | Randy Lerch | Howard Bailey | Randy Lerch | Howard Bailey | | 191 | 174 | 17 |
| 1981-05-28 | vs DET | 43 | W 7-1 | - | | 15,943 | Mike Caldwell | Dan Petry | Mike Caldwell | Dan Petry | Rollie Fingers | 198 | 175 | 23 |
| 1981-05-29 | @ BOS | 44 | W 5-4 | - | | 22,794 | Jim Slaton | Mike Torrez | Rollie Fingers | Tom Burgmeier | | 203 | 179 | 24 |
| 1981-05-30 | @ BOS | 45 | L 6-7 | - | | 23,718 | Moose Haas | Frank Tanana | Mark Clear | Rollie Fingers | | 209 | 186 | 23 |
| 1981-05-31 | @ BOS | 46 | W 5-2 | - | | 23,781 | Pete Vuckovich | Steve Crawford | Pete Vuckovich | Steve Crawford | | 214 | 188 | 26 |
| 1981-06-01 | @ DET | 47 | L 3-4 | - | | 14,495 | Randy Lerch | Milt Wilcox | Dave Rozema | Reggie Cleveland | | 217 | 192 | 25 |
| 1981-06-02 | @ DET | 48 | W 5-2 | - | | 14,079 | Mike Caldwell | Dan Petry | Mike Caldwell | Dan Petry | Rollie Fingers | 222 | 194 | 28 |
| 1981-06-03 | @ DET | 49 | L 1-4 | - | | 13,392 | Jim Slaton | Dan Schatzeder | Dan Schatzeder | Jim Slaton | Kevin Saucier | 223 | 198 | 25 |
| 1981-06-05 | @ KCA | 50 | W 6-2 | - | | 31,300 | Moose Haas | Larry Gura | Moose Haas | Larry Gura | | 229 | 200 | 29 |
| 1981-06-06 | @ KCA | 51 | W 4-2 | - | | 37,468 | Pete Vuckovich | Dennis Leonard | Pete Vuckovich | Dennis Leonard | Rollie Fingers | 233 | 202 | 31 |
| 1981-06-07 | @ KCA | 52 | L 1-7 | - | | 32,429 | Randy Lerch | Paul Splittorff | Paul Splittorff | Randy Lerch | Renie Martin | 234 | 209 | 25 |
| 1981-06-08 | @ MIN | 53 | L 0-1 | - | | 11,978 | Mike Caldwell | Roger Erickson | Roger Erickson | Mike Caldwell | Doug Corbett | 234 | 210 | 24 |
| 1981-06-09 | @ MIN | 54 | L 1-3 | - | | 9,731 | Jim Slaton | Fernando Arroyo | Fernando Arroyo | Jim Slaton | Doug Corbett | 235 | 213 | 22 |
| 1981-06-10 | vs TEX | 55 | L 5-12 | - | | 19,189 | Moose Haas | Doc Medich | Doc Medich | Moose Haas | | 240 | 225 | 15 |
| 1981-06-11 | vs TEX | 56 | W 6-3 | - | | 15,259 | Pete Vuckovich | Fergie Jenkins | Pete Vuckovich | Fergie Jenkins | Rollie Fingers | 246 | 228 | 18 |
| 1981-08-10 | @ CLE | 57 | W 5-2 | - | | 4,773 | Pete Vuckovich | Bert Blyleven | Rickey Keeton | Mike Stanton | | 251 | 230 | 21 |
| 1981-08-11 | @ CLE | 58 | W 6-5 | - | | 0 | Mike Caldwell | John Denny | Mike Caldwell | John Denny | Jamie Easterly | 257 | 235 | 22 |
| 1981-08-11 | @ CLE | 59 | W 6-1 | - | | 7,776 | Jim Slaton | Rick Waits | Jim Slaton | Rick Waits | Jerry Augustine | 263 | 236 | 27 |
| 1981-08-12 | @ CLE | 60 | L 4-9 | - | | 5,819 | Randy Lerch | Len Barker | Len Barker | Randy Lerch | | 267 | 245 | 22 |
| 1981-08-13 | @ CLE | 61 | W 8-5 | - | | 5,639 | Moose Haas | Wayne Garland | Moose Haas | Wayne Garland | Rollie Fingers | 275 | 250 | 25 |
| 1981-08-14 | @ TOR | 62 | L 4-5 | - | | 15,114 | Pete Vuckovich | Jim Clancy | Jerry Garvin | Jamie Easterly | Roy Lee Jackson | 279 | 255 | 24 |
| 1981-08-15 | @ TOR | 63 | L 3-4 | - | | 12,467 | Jim Slaton | Juan Berenguer | Mark Bomback | Reggie Cleveland | Joey McLaughlin | 282 | 259 | 23 |
| 1981-08-16 | @ TOR | 64 | W 6-2 | - | | 0 | Mike Caldwell | Dave Stieb | Mike Caldwell | Dave Stieb | Rollie Fingers | 288 | 261 | 27 |
| 1981-08-16 | @ TOR | 65 | W 2-0 | - | | 24,472 | Randy Lerch | Jackson Todd | Randy Lerch | Jackson Todd | Rollie Fingers | 290 | 261 | 29 |
| 1981-08-18 | @ TEX | 66 | W 3-1 | - | | 0 | Moose Haas | Jon Matlack | Moose Haas | Jon Matlack | Rollie Fingers | 293 | 262 | 31 |
| 1981-08-18 | @ TEX | 67 | L 6-8 | - | | 37,310 | Pete Vuckovich | Fergie Jenkins | Steve Comer | Pete Vuckovich | Jim Kern | 299 | 270 | 29 |
| 1981-08-19 | @ TEX | 68 | L 1-4 | - | | 13,908 | Jim Slaton | Doc Medich | Doc Medich | Jim Slaton | Jim Kern | 300 | 274 | 26 |
| 1981-08-21 | vs MIN | 69 | L 6-7 | - | | 30,123 | Mike Caldwell | Albert Williams | Albert Williams | Mike Caldwell | Jerry Koosman | 306 | 281 | 25 |
| 1981-08-22 | vs MIN | 70 | W 4-3 | - | | 15,292 | Randy Lerch | Pete Redfern | Rollie Fingers | Don Cooper | | 310 | 284 | 26 |
| 1981-08-23 | vs MIN | 71 | W 8-5 | - | | 18,724 | Moose Haas | Fernando Arroyo | Jerry Augustine | Fernando Arroyo | Rollie Fingers | 318 | 289 | 29 |
| 1981-08-24 | vs CHA | 72 | W 5-4 | - | | 16,809 | Pete Vuckovich | Richard Dotson | Pete Vuckovich | Richard Dotson | Reggie Cleveland | 323 | 293 | 30 |
| 1981-08-25 | vs CHA | 73 | L 1-5 | - | | 16,331 | Jim Slaton | Dennis Lamp | Dennis Lamp | Jim Slaton | | 324 | 298 | 26 |
| 1981-08-27 | vs TEX | 74 | L 1-5 | - | | 8,908 | Mike Caldwell | Danny Darwin | Danny Darwin | Mike Caldwell | | 325 | 303 | 22 |
| 1981-08-28 | vs TEX | 75 | W 6-3 | - | | 17,072 | Moose Haas | Rick Honeycutt | Moose Haas | Rick Honeycutt | Rollie Fingers | 331 | 306 | 25 |
| 1981-08-29 | vs TEX | 76 | L 5-8 | - | | 15,536 | Randy Lerch | Jon Matlack | Jon Matlack | Randy Lerch | Jim Kern | 336 | 314 | 22 |
| 1981-08-30 | vs TEX | 77 | W 6-2 | - | | 14,722 | Pete Vuckovich | Doc Medich | Pete Vuckovich | Doc Medich | Rollie Fingers | 342 | 316 | 26 |
| 1981-08-31 | @ KCA | 78 | W 5-1 | - | | 27,974 | Mike Caldwell | Dennis Leonard | Mike Caldwell | Dennis Leonard | Rollie Fingers | 347 | 317 | 30 |
| 1981-09-01 | @ KCA | 79 | L 1-3 | - | | 22,202 | Moose Haas | Larry Gura | Larry Gura | Moose Haas | | 348 | 320 | 28 |
| 1981-09-02 | @ KCA | 80 | L 4-5 | - | | 19,658 | Randy Lerch | Atlee Hammaker | Dan Quisenberry | Rollie Fingers | | 352 | 325 | 27 |
| 1981-09-03 | @ MIN | 81 | W 4-3 | - | | 5,257 | Pete Vuckovich | Brad Havens | Pete Vuckovich | Brad Havens | Rollie Fingers | 356 | 328 | 28 |
| 1981-09-04 | @ MIN | 82 | W 16-5 | - | | 7,976 | Mike Caldwell | Fernando Arroyo | Mike Caldwell | Fernando Arroyo | | 372 | 333 | 39 |
| 1981-09-05 | @ MIN | 83 | W 5-3 | - | | 9,952 | Jim Slaton | Albert Williams | Jim Slaton | Albert Williams | Rollie Fingers | 377 | 336 | 41 |
| 1981-09-06 | @ MIN | 84 | W 8-7 | - | | 9,764 | Moose Haas | Pete Redfern | Rollie Fingers | Doug Corbett | | 385 | 343 | 42 |
| 1981-09-07 | @ NYA | 85 | L 2-4 | - | | 55,083 | Randy Lerch | Ron Guidry | Ron Guidry | Randy Lerch | Rich Gossage | 387 | 347 | 40 |
| 1981-09-09 | @ NYA | 86 | L 2-5 | - | | 0 | Pete Vuckovich | Tommy John | Tommy John | Pete Vuckovich | | 389 | 352 | 37 |
| 1981-09-09 | @ NYA | 87 | W 5-3 | - | | 27,337 | Mike Caldwell | Rudy May | Mike Caldwell | Rudy May | Rollie Fingers | 394 | 355 | 39 |
| 1981-09-10 | vs CHA | 88 | L 6-12 | - | | 9,268 | Jim Slaton | Ross Baumgarten | LaMarr Hoyt | Reggie Cleveland | | 400 | 367 | 33 |
| 1981-09-11 | vs BAL | 89 | L 1-2 | - | | 20,987 | Moose Haas | Dennis Martinez | Dennis Martinez | Moose Haas | | 401 | 369 | 32 |
| 1981-09-12 | vs BAL | 90 | W 6-3 | - | | 25,398 | Randy Lerch | Jim Palmer | Randy Lerch | Jim Palmer | Rollie Fingers | 407 | 372 | 35 |
| 1981-09-13 | vs BAL | 91 | W 5-0 | - | | 19,599 | Pete Vuckovich | Steve Stone | Pete Vuckovich | Steve Stone | | 412 | 372 | 40 |
| 1981-09-14 | vs NYA | 92 | L 2-10 | - | | 17,545 | Mike Caldwell | Tommy John | Tommy John | Mike Caldwell | | 414 | 382 | 32 |
| 1981-09-15 | vs NYA | 93 | W 2-1 | - | | 15,402 | Moose Haas | Rudy May | Moose Haas | Rudy May | Rollie Fingers | 416 | 383 | 33 |
| 1981-09-16 | vs NYA | 94 | W 3-2 | - | | 13,510 | Randy Lerch | Dave Righetti | Randy Lerch | Dave Righetti | Rollie Fingers | 419 | 385 | 34 |
| 1981-09-18 | @ BAL | 95 | W 5-1 | - | | 17,190 | Pete Vuckovich | Mike Flanagan | Pete Vuckovich | Mike Flanagan | Jamie Easterly | 424 | 386 | 38 |
| 1981-09-19 | @ BAL | 96 | W 11-8 | - | | 18,380 | Jim Slaton | Dennis Martinez | Rollie Fingers | Tippy Martinez | | 435 | 394 | 41 |
| 1981-09-20 | @ BAL | 97 | L 2-8 | - | | 17,457 | Mike Caldwell | Jim Palmer | Jim Palmer | Mike Caldwell | | 437 | 402 | 35 |
| 1981-09-21 | @ BOS | 98 | L 3-9 | - | | 14,575 | Moose Haas | Dennis Eckersley | Dennis Eckersley | Moose Haas | | 440 | 411 | 29 |
| 1981-09-22 | @ BOS | 99 | W 10-8 | - | | 18,363 | Pete Vuckovich | Bob Ojeda | Rollie Fingers | Mark Clear | | 450 | 419 | 31 |
| 1981-09-23 | @ BOS | 100 | L 5-11 | - | | 15,627 | Jim Slaton | Frank Tanana | Luis Aponte | Jamie Easterly | | 455 | 430 | 25 |
| 1981-09-25 | @ DET | 101 | W 8-6 | - | | 35,003 | Mike Caldwell | Jack Morris | Jamie Easterly | Jack Morris | Rollie Fingers | 463 | 436 | 27 |
| 1981-09-26 | @ DET | 102 | W 4-3 | - | | 29,759 | Moose Haas | Milt Wilcox | Moose Haas | Milt Wilcox | Rollie Fingers | 467 | 439 | 28 |
| 1981-09-27 | @ DET | 103 | L 1-2 | - | | 32,185 | Randy Lerch | Dan Petry | Dan Petry | Randy Lerch | | 468 | 441 | 27 |
| 1981-09-28 | vs BOS | 104 | W 1-0 | - | | 11,334 | Pete Vuckovich | Frank Tanana | Pete Vuckovich | Frank Tanana | | 469 | 441 | 28 |
| 1981-09-29 | vs BOS | 105 | L 2-7 | - | | 12,654 | Jim Slaton | Mike Torrez | Mike Torrez | Jim Slaton | | 471 | 448 | 23 |
| 1981-09-30 | vs BOS | 106 | W 10-5 | - | | 11,472 | Mike Caldwell | Bruce Hurst | Randy Lerch | Bob Stanley | | 481 | 453 | 28 |
| 1981-10-02 | vs DET | 107 | W 8-2 | - | | 23,540 | Moose Haas | Dan Petry | Moose Haas | Dan Petry | | 489 | 455 | 34 |
| 1981-10-03 | vs DET | 108 | W 2-1 | - | | 28,330 | Pete Vuckovich | Jack Morris | Rollie Fingers | Jack Morris | | 491 | 456 | 35 |
| 1981-10-04 | vs DET | 109 | L 2-3 | - | | 15,263 | Randy Lerch | Milt Wilcox | Milt Wilcox | Jerry Augustine | | 493 | 459 | 34 |