| 1981-04-10 | @ BOS | 1 | W 5-3 | 1-0 | 1 | 35,154 | Britt Burns | Dennis Eckersley | LaMarr Hoyt | Bob Stanley | Ed Farmer | 5 | 3 | 2 |
| 1981-04-12 | @ BOS | 2 | L 4-5 | 1-1 | 3 | 21,439 | Richard Dotson | Frank Tanana | Mark Clear | Ed Farmer | | 9 | 8 | 1 |
| 1981-04-14 | vs MIL | 3 | W 9-3 | 2-1 | 2 | 51,560 | Ross Baumgarten | Pete Vuckovich | Ross Baumgarten | Pete Vuckovich | | 18 | 11 | 7 |
| 1981-04-15 | vs MIL | 4 | W 5-4 | 3-1 | 2 | 13,212 | Britt Burns | Moose Haas | LaMarr Hoyt | Rollie Fingers | | 23 | 15 | 8 |
| 1981-04-17 | vs BOS | 5 | L 5-8 | 3-2 | 2 | 30,458 | Richard Dotson | Dennis Eckersley | Dennis Eckersley | Richard Dotson | Tom Burgmeier | 28 | 23 | 5 |
| 1981-04-18 | vs BOS | 6 | W 2-1 | 4-2 | 2 | 36,782 | Steve Trout | Frank Tanana | Steve Trout | Frank Tanana | LaMarr Hoyt | 30 | 24 | 6 |
| 1981-04-19 | vs BOS | 7 | L 4-9 | 4-3 | 2 | 9,528 | Ross Baumgarten | Steve Crawford | Bob Stanley | Ross Baumgarten | Tom Burgmeier | 34 | 33 | 1 |
| 1981-04-21 | vs BAL | 8 | W 2-1 | 5-3 | 2 | 10,715 | Britt Burns | Jim Palmer | Britt Burns | Sammy Stewart | | 36 | 34 | 2 |
| 1981-04-23 | vs BAL | 9 | W 18-5 | 7-3 | 2 | 0 | Richard Dotson | Scott McGregor | Richard Dotson | Scott McGregor | | 54 | 39 | 15 |
| 1981-04-23 | vs BAL | 10 | W 5-3 | 7-3 | 2 | 6,839 | Francisco Barrios | Steve Stone | Francisco Barrios | Steve Stone | Ed Farmer | 59 | 42 | 17 |
| 1981-04-24 | @ DET | 11 | W 3-2 | 8-3 | 2 | 13,483 | Steve Trout | Jack Morris | LaMarr Hoyt | Jack Morris | | 62 | 44 | 18 |
| 1981-04-25 | @ DET | 12 | W 4-0 | 9-3 | 2 | 14,862 | Ross Baumgarten | Dave Rozema | Ross Baumgarten | Dave Rozema | LaMarr Hoyt | 66 | 44 | 22 |
| 1981-04-26 | @ DET | 13 | W 5-4 | 10-3 | 2 | 13,410 | Britt Burns | Milt Wilcox | Britt Burns | Milt Wilcox | Ed Farmer | 71 | 48 | 23 |
| 1981-04-27 | @ BAL | 14 | L 2-5 | 10-4 | 2 | 11,774 | Francisco Barrios | Scott McGregor | Scott McGregor | Francisco Barrios | Tippy Martinez | 73 | 53 | 20 |
| 1981-04-28 | @ BAL | 15 | W 8-6 | 11-4 | 2 | 9,883 | Richard Dotson | Steve Stone | Richard Dotson | Steve Stone | Ed Farmer | 81 | 59 | 22 |
| 1981-04-29 | @ BAL | 16 | L 0-3 | 11-5 | 2 | 9,957 | Steve Trout | Dennis Martinez | Dennis Martinez | Steve Trout | Tippy Martinez | 81 | 62 | 19 |
| 1981-04-30 | @ CLE | 17 | L 2-3 | 11-6 | 2 | 6,639 | Ross Baumgarten | Rick Waits | Rick Waits | Ross Baumgarten | | 83 | 65 | 18 |
| 1981-05-01 | @ CLE | 18 | L 2-10 | 11-7 | 2 | 9,142 | Britt Burns | John Denny | John Denny | Britt Burns | | 85 | 75 | 10 |
| 1981-05-02 | @ CLE | 19 | L 1-3 | 11-8 | 2 | 11,618 | Francisco Barrios | Len Barker | Len Barker | Francisco Barrios | | 86 | 78 | 8 |
| 1981-05-03 | @ CLE | 20 | W 6-0 | 12-8 | 2 | 31,287 | Richard Dotson | Wayne Garland | Richard Dotson | Wayne Garland | | 92 | 78 | 14 |
| 1981-05-05 | @ TEX | 21 | L 1-6 | 12-9 | 2 | 10,399 | Ross Baumgarten | Danny Darwin | Danny Darwin | Ross Baumgarten | | 93 | 84 | 9 |
| 1981-05-06 | @ TEX | 22 | L 2-4 | 12-10 | 3 | 12,104 | Britt Burns | Rick Honeycutt | John Henry Johnson | Britt Burns | | 95 | 88 | 7 |
| 1981-05-07 | @ TEX | 23 | L 4-9 | 12-11 | 3 | 11,710 | Steve Trout | Jon Matlack | Bob Babcock | Ed Farmer | | 99 | 97 | 2 |
| 1981-05-08 | vs KCA | 24 | W 9-5 | 13-11 | 3 | 42,312 | Francisco Barrios | Paul Splittorff | Dennis Lamp | Paul Splittorff | LaMarr Hoyt | 108 | 102 | 6 |
| 1981-05-09 | vs KCA | 25 | W 3-0 | 14-11 | 2 | 23,706 | Richard Dotson | Rich Gale | Richard Dotson | Rich Gale | | 111 | 102 | 9 |
| 1981-05-11 | vs CLE | 26 | L 1-3 | 14-12 | 3 | 16,806 | Ross Baumgarten | Bert Blyleven | Bert Blyleven | Ross Baumgarten | | 112 | 105 | 7 |
| 1981-05-12 | vs CLE | 27 | W 7-4 | 15-12 | 3 | 13,263 | Steve Trout | Rick Waits | Steve Trout | Rick Waits | LaMarr Hoyt | 119 | 109 | 10 |
| 1981-05-13 | vs CLE | 28 | L 3-4 | 15-13 | 3 | 10,463 | Francisco Barrios | John Denny | Mike Stanton | Dennis Lamp | | 122 | 113 | 9 |
| 1981-05-15 | vs TEX | 29 | L 1-2 | 15-14 | 3 | 29,829 | Richard Dotson | Fergie Jenkins | Fergie Jenkins | Richard Dotson | Steve Comer | 123 | 115 | 8 |
| 1981-05-16 | vs TEX | 30 | W 9-1 | 16-14 | 3 | 20,206 | Britt Burns | Danny Darwin | Britt Burns | Danny Darwin | | 132 | 116 | 16 |
| 1981-05-17 | vs TEX | 31 | W 9-0 | 17-14 | 3 | 30,990 | Ross Baumgarten | Rick Honeycutt | Ross Baumgarten | Rick Honeycutt | | 141 | 116 | 25 |
| 1981-05-18 | @ TOR | 32 | W 7-2 | 18-14 | 3 | 18,652 | Steve Trout | Mark Bomback | Steve Trout | Mark Bomback | | 148 | 118 | 30 |
| 1981-05-19 | @ TOR | 33 | L 5-9 | 18-15 | 3 | 11,604 | Francisco Barrios | Jim Clancy | Jim Clancy | LaMarr Hoyt | Luis Leal | 153 | 127 | 26 |
| 1981-05-20 | @ TOR | 34 | W 6-5 | 19-15 | 2 | 12,536 | Richard Dotson | Jackson Todd | Ed Farmer | Joey McLaughlin | LaMarr Hoyt | 159 | 132 | 27 |
| 1981-05-22 | @ CAL | 35 | W 9-5 | 20-15 | 2 | 27,919 | Britt Burns | Ken Forsch | Britt Burns | Ken Forsch | Ed Farmer | 168 | 137 | 31 |
| 1981-05-23 | @ CAL | 36 | W 15-4 | 21-15 | 2 | 42,558 | Ross Baumgarten | Steve Renko | Ross Baumgarten | Steve Renko | | 183 | 141 | 42 |
| 1981-05-24 | @ CAL | 37 | W 10-2 | 22-15 | 2 | 27,405 | Steve Trout | Geoff Zahn | Steve Trout | Geoff Zahn | | 193 | 143 | 50 |
| 1981-05-25 | @ OAK | 38 | L 2-5 | 22-16 | 3 | 40,689 | Richard Dotson | Steve McCatty | Steve McCatty | Richard Dotson | | 195 | 148 | 47 |
| 1981-05-26 | @ OAK | 39 | W 4-1 | 23-16 | 3 | 26,371 | Britt Burns | Brian Kingman | Britt Burns | Brian Kingman | | 199 | 149 | 50 |
| 1981-05-27 | @ OAK | 40 | W 3-0 | 24-16 | 2 | 17,621 | Ross Baumgarten | Rick Langford | Ross Baumgarten | Rick Langford | LaMarr Hoyt | 202 | 149 | 53 |
| 1981-05-30 | vs CAL | 41 | W 9-0 | 25-16 | 1 | 16,773 | Richard Dotson | Geoff Zahn | Richard Dotson | Geoff Zahn | | 211 | 149 | 62 |
| 1981-05-31 | vs CAL | 42 | L 4-7 | 26-17 | 2 | 0 | Steve Trout | Mike Witt | Mike Witt | Steve Trout | | 215 | 156 | 59 |
| 1981-05-31 | vs CAL | 43 | W 2-1 | 26-17 | 2 | 40,248 | Britt Burns | Steve Renko | LaMarr Hoyt | Don Aase | | 217 | 157 | 60 |
| 1981-06-02 | vs OAK | 44 | L 2-6 | 26-18 | 2 | 40,045 | Ross Baumgarten | Steve McCatty | Steve McCatty | Ross Baumgarten | | 219 | 163 | 56 |
| 1981-06-03 | vs OAK | 45 | L 3-8 | 26-19 | 3 | 42,358 | Francisco Barrios | Brian Kingman | Brian Kingman | Francisco Barrios | | 222 | 171 | 51 |
| 1981-06-04 | vs OAK | 46 | W 4-2 | 27-19 | 2 | 37,706 | Richard Dotson | Rick Langford | Richard Dotson | Rick Langford | Ed Farmer | 226 | 173 | 53 |
| 1981-06-05 | @ NYA | 47 | L 5-6 | 27-20 | 3 | 35,707 | Britt Burns | Rudy May | Dave LaRoche | Kevin Hickey | | 231 | 179 | 52 |
| 1981-06-06 | @ NYA | 48 | L 0-2 | 27-21 | 3 | 36,255 | Steve Trout | Doug Bird | Doug Bird | Steve Trout | Rich Gossage | 231 | 181 | 50 |
| 1981-06-07 | @ NYA | 49 | L 1-3 | 27-22 | 3 | 52,367 | Ross Baumgarten | Ron Guidry | Ron Guidry | Ross Baumgarten | Rich Gossage | 232 | 184 | 48 |
| 1981-06-08 | vs TOR | 50 | W 6-2 | 28-22 | 3 | 8,301 | Dennis Lamp | Jim Clancy | Dennis Lamp | Jim Clancy | Kevin Hickey | 238 | 186 | 52 |
| 1981-06-09 | vs TOR | 51 | W 3-0 | 29-22 | 3 | 8,534 | Richard Dotson | Luis Leal | Richard Dotson | Luis Leal | | 241 | 186 | 55 |
| 1981-06-10 | vs NYA | 52 | W 6-5 | 30-22 | 3 | 33,647 | Britt Burns | Rudy May | Britt Burns | Rudy May | Ed Farmer | 247 | 191 | 56 |
| 1981-06-11 | vs NYA | 53 | W 3-2 | 31-22 | 3 | 33,777 | Steve Trout | Doug Bird | Steve Trout | Doug Bird | LaMarr Hoyt | 250 | 193 | 57 |
| 1981-08-10 | @ BOS | 54 | W 7-1 | 32-22 | 2 | 20,227 | Richard Dotson | Dennis Eckersley | Dennis Lamp | Dennis Eckersley | | 257 | 194 | 63 |
| 1981-08-11 | @ BOS | 55 | W 4-2 | 33-22 | 2 | 17,889 | Ross Baumgarten | Mike Torrez | Steve Trout | Bob Stanley | Ed Farmer | 261 | 196 | 65 |
| 1981-08-12 | @ BOS | 56 | L 1-8 | 33-23 | 2 | 20,257 | Britt Burns | Bob Ojeda | Bob Ojeda | LaMarr Hoyt | | 262 | 204 | 58 |
| 1981-08-13 | @ BOS | 57 | L 6-9 | 33-24 | 3 | 18,683 | Reggie Patterson | Steve Crawford | Mark Clear | Reggie Patterson | Bill Campbell | 268 | 213 | 55 |
| 1981-08-14 | @ BAL | 58 | W 5-3 | 34-24 | 3 | 15,401 | Richard Dotson | Sammy Stewart | Richard Dotson | Sammy Stewart | Ed Farmer | 273 | 216 | 57 |
| 1981-08-15 | @ BAL | 59 | L 0-4 | 34-25 | 3 | 15,323 | LaMarr Hoyt | Dennis Martinez | Dennis Martinez | LaMarr Hoyt | | 273 | 220 | 53 |
| 1981-08-16 | @ BAL | 60 | W 8-7 | 35-25 | 3 | 16,684 | Ross Baumgarten | Jim Palmer | Ed Farmer | Dave Ford | Kevin Hickey | 281 | 227 | 54 |
| 1981-08-17 | @ NYA | 61 | W 4-1 | 36-25 | 2 | 24,651 | Britt Burns | Rick Reuschel | Britt Burns | Rick Reuschel | Kevin Hickey | 285 | 228 | 57 |
| 1981-08-18 | @ NYA | 62 | L 0-4 | 36-26 | 3 | 30,157 | Steve Trout | Ron Guidry | Ron Guidry | Steve Trout | George Frazier | 285 | 232 | 53 |
| 1981-08-19 | @ NYA | 63 | W 6-5 | 37-26 | 3 | 30,421 | Richard Dotson | Tommy John | Dennis Lamp | Rudy May | Ed Farmer | 291 | 237 | 54 |
| 1981-08-21 | @ TOR | 64 | L 4-5 | 37-27 | 3 | 14,161 | Ross Baumgarten | Dave Stieb | Dave Stieb | Ed Farmer | | 295 | 242 | 53 |
| 1981-08-22 | @ TOR | 65 | W 8-0 | 38-27 | 2 | 19,080 | Britt Burns | Jim Clancy | Britt Burns | Jim Clancy | | 303 | 242 | 61 |
| 1981-08-23 | @ TOR | 66 | W 13-2 | 39-27 | 2 | 16,486 | Steve Trout | Luis Leal | Steve Trout | Luis Leal | | 316 | 244 | 72 |
| 1981-08-24 | @ MIL | 67 | L 4-5 | 39-28 | 2 | 16,809 | Richard Dotson | Pete Vuckovich | Pete Vuckovich | Richard Dotson | Reggie Cleveland | 320 | 249 | 71 |
| 1981-08-25 | @ MIL | 68 | W 5-1 | 40-28 | 2 | 16,331 | Dennis Lamp | Jim Slaton | Dennis Lamp | Jim Slaton | | 325 | 250 | 75 |
| 1981-08-27 | vs NYA | 69 | W 3-1 | 41-28 | 2 | 30,787 | Britt Burns | Rick Reuschel | LaMarr Hoyt | Ron Davis | | 328 | 251 | 77 |
| 1981-08-28 | vs NYA | 70 | L 1-6 | 41-29 | 2 | 33,390 | Steve Trout | Ron Guidry | Ron Guidry | Steve Trout | | 329 | 257 | 72 |
| 1981-08-29 | vs NYA | 71 | L 2-12 | 41-30 | 3 | 32,507 | Richard Dotson | Tommy John | Tommy John | Richard Dotson | | 331 | 269 | 62 |
| 1981-08-30 | vs NYA | 72 | L 1-5 | 41-31 | 3 | 33,213 | Dennis Lamp | Rudy May | Rudy May | Dennis Lamp | | 332 | 274 | 58 |
| 1981-08-31 | vs DET | 73 | L 1-3 | 41-32 | 3 | 13,057 | Ross Baumgarten | Milt Wilcox | Milt Wilcox | Ross Baumgarten | | 333 | 277 | 56 |
| 1981-09-01 | vs DET | 74 | L 1-2 | 41-33 | 3 | 9,775 | Britt Burns | Dan Petry | Dan Petry | Jerry Koosman | | 334 | 279 | 55 |
| 1981-09-02 | vs DET | 75 | L 4-5 | 41-34 | 3 | 10,272 | Richard Dotson | Jerry Ujdur | Kevin Saucier | Jerry Koosman | Dave Rozema | 338 | 284 | 54 |
| 1981-09-03 | vs TOR | 76 | W 4-3 | 42-34 | 3 | 6,669 | Steve Trout | Juan Berenguer | LaMarr Hoyt | Juan Berenguer | | 342 | 287 | 55 |
| 1981-09-04 | vs TOR | 77 | L 2-6 | 42-35 | 3 | 18,317 | Dennis Lamp | Dave Stieb | Dave Stieb | Dennis Lamp | | 344 | 293 | 51 |
| 1981-09-05 | vs TOR | 78 | L 1-3 | 42-36 | 3 | 14,628 | Ross Baumgarten | Jim Clancy | Jim Clancy | Ross Baumgarten | Joey McLaughlin | 345 | 296 | 49 |
| 1981-09-06 | vs TOR | 79 | L 2-3 | 42-37 | 3 | 11,250 | Britt Burns | Luis Leal | Luis Leal | Britt Burns | Roy Lee Jackson | 347 | 299 | 48 |
| 1981-09-07 | vs SEA | 80 | L 5-9 | 42-38 | 3 | 16,392 | Richard Dotson | Jim Beattie | Jim Beattie | Richard Dotson | Larry Andersen | 352 | 308 | 44 |
| 1981-09-08 | vs SEA | 81 | W 5-3 | 43-38 | 3 | 11,561 | Steve Trout | Floyd Bannister | Steve Trout | Floyd Bannister | LaMarr Hoyt | 357 | 311 | 46 |
| 1981-09-09 | vs SEA | 82 | L 1-3 | 43-39 | 3 | 8,238 | Dennis Lamp | Bob Stoddard | Bob Stoddard | Dennis Lamp | Larry Andersen | 358 | 314 | 44 |
| 1981-09-10 | @ MIL | 83 | W 12-6 | 44-39 | 3 | 9,268 | Ross Baumgarten | Jim Slaton | LaMarr Hoyt | Reggie Cleveland | | 370 | 320 | 50 |
| 1981-09-11 | @ MIN | 84 | L 3-4 | 44-40 | 3 | 6,954 | Britt Burns | Albert Williams | Albert Williams | Britt Burns | Doug Corbett | 373 | 324 | 49 |
| 1981-09-12 | @ MIN | 85 | L 1-3 | 44-41 | 3 | 7,967 | Richard Dotson | Pete Redfern | Pete Redfern | Richard Dotson | Doug Corbett | 374 | 327 | 47 |
| 1981-09-13 | @ MIN | 86 | L 6-7 | 44-42 | 3 | 16,308 | Steve Trout | Don Cooper | Bob Veselic | Kevin Hickey | | 380 | 334 | 46 |
| 1981-09-14 | @ SEA | 87 | W 5-2 | 45-42 | 3 | 4,778 | Dennis Lamp | Floyd Bannister | Dennis Lamp | Floyd Bannister | | 385 | 336 | 49 |
| 1981-09-15 | @ SEA | 88 | L 4-8 | 45-43 | 3 | 5,024 | Jerry Koosman | Bob Stoddard | Larry Andersen | Jerry Koosman | Dick Drago | 389 | 344 | 45 |
| 1981-09-16 | @ SEA | 89 | W 3-1 | 46-43 | 3 | 5,178 | Britt Burns | Ken Clay | Britt Burns | Dick Drago | | 392 | 345 | 47 |
| 1981-09-18 | vs OAK | 90 | L 5-10 | 46-44 | 3 | 21,266 | Steve Trout | Steve McCatty | Steve McCatty | Steve Trout | Dave Beard | 397 | 355 | 42 |
| 1981-09-19 | vs OAK | 91 | L 1-2 | 46-45 | 3 | 13,213 | Dennis Lamp | Rick Langford | Rick Langford | Dennis Lamp | | 398 | 357 | 41 |
| 1981-09-20 | vs OAK | 92 | W 11-3 | 47-45 | 3 | 17,819 | Richard Dotson | Mike Norris | Richard Dotson | Mike Norris | LaMarr Hoyt | 409 | 360 | 49 |
| 1981-09-21 | @ CAL | 93 | L 3-6 | 47-46 | 3 | 21,049 | Britt Burns | Steve Renko | Steve Renko | Britt Burns | Don Aase | 412 | 366 | 46 |
| 1981-09-22 | @ CAL | 94 | L 0-1 | 47-47 | 3 | 19,826 | Ross Baumgarten | Angel Moreno | Angel Moreno | Ross Baumgarten | Don Aase | 412 | 367 | 45 |
| 1981-09-23 | @ CAL | 95 | L 3-7 | 47-48 | 3 | 19,639 | Steve Trout | Mike Witt | Mike Witt | Steve Trout | | 415 | 374 | 41 |
| 1981-09-24 | @ CAL | 96 | W 4-1 | 48-48 | 3 | 19,156 | Dennis Lamp | Bruce Kison | Dennis Lamp | Bruce Kison | | 419 | 375 | 44 |
| 1981-09-25 | @ OAK | 97 | W 6-2 | 49-48 | 3 | 21,468 | Richard Dotson | Mike Norris | Ed Farmer | Mike Norris | | 425 | 377 | 48 |
| 1981-09-26 | @ OAK | 98 | L 1-5 | 49-49 | 3 | 21,171 | Britt Burns | Steve McCatty | Steve McCatty | Britt Burns | | 426 | 382 | 44 |
| 1981-09-27 | @ OAK | 99 | W 9-5 | 51-49 | 3 | 0 | Ross Baumgarten | Rick Langford | LaMarr Hoyt | Rick Langford | | 435 | 387 | 48 |
| 1981-09-27 | @ OAK | 100 | W 10-3 | 51-49 | 3 | 25,377 | Jerry Koosman | Matt Keough | Jerry Koosman | Matt Keough | | 445 | 390 | 55 |
| 1981-09-28 | vs CAL | 101 | L 0-6 | 51-50 | 3 | 3,129 | Dennis Lamp | Mike Witt | Mike Witt | Dennis Lamp | | 445 | 396 | 49 |
| 1981-09-29 | vs CAL | 102 | L 1-5 | 51-51 | 3 | 5,630 | Richard Dotson | Bruce Kison | Bruce Kison | Richard Dotson | Steve Renko | 446 | 401 | 45 |
| 1981-09-30 | vs CAL | 103 | W 10-3 | 52-51 | 3 | 5,674 | Britt Burns | Dave Frost | Britt Burns | Dave Frost | LaMarr Hoyt | 456 | 404 | 52 |
| 1981-10-02 | vs MIN | 104 | L 2-3 | 52-52 | 3 | 7,175 | Jerry Koosman | Pete Redfern | Pete Redfern | Jerry Koosman | Doug Corbett | 458 | 407 | 51 |
| 1981-10-03 | vs MIN | 105 | W 5-4 | 53-52 | 3 | 4,716 | Dennis Lamp | Brad Havens | LaMarr Hoyt | Bob Veselic | | 463 | 411 | 52 |
| 1981-10-04 | vs MIN | 106 | W 13-12 | 54-52 | 3 | 7,965 | Richard Dotson | Albert Williams | Dewey Robinson | Doug Corbett | | 476 | 423 | 53 |