| 1981-04-09 | vs NYN | 1 | L 0-2 | 0-1 | 3 | 37,030 | Rick Reuschel | Pat Zachry | Pat Zachry | Rick Reuschel | Neil Allen | 0 | 2 | -2 |
| 1981-04-11 | vs NYN | 2 | W 3-1 | 1-1 | 2 | 12,114 | Lynn McGlothen | Randy Jones | Dick Tidrow | Tom Hausman | | 3 | 3 | 0 |
| 1981-04-12 | vs NYN | 3 | L 1-2 | 1-2 | 5 | 7,475 | Ken Kravec | Tim Leary | Neil Allen | Rawly Eastwick | | 4 | 5 | -1 |
| 1981-04-15 | @ MON | 4 | L 4-5 | 1-3 | 5 | 30,003 | Rick Reuschel | Steve Rogers | Stan Bahnsen | Dick Tidrow | | 8 | 10 | -2 |
| 1981-04-16 | @ MON | 5 | L 0-7 | 1-4 | 5 | 11,602 | Lynn McGlothen | Scott Sanderson | Scott Sanderson | Lynn McGlothen | | 8 | 17 | -9 |
| 1981-04-17 | @ PHI | 6 | L 2-6 | 1-5 | 6 | 21,948 | Ken Kravec | Larry Christenson | Larry Christenson | Ken Kravec | | 10 | 23 | -13 |
| 1981-04-18 | @ PHI | 7 | L 3-4 | 1-6 | 6 | 27,780 | Mike Krukow | Steve Carlton | Steve Carlton | Lee Smith | | 13 | 27 | -14 |
| 1981-04-19 | @ PHI | 8 | L 3-7 | 1-7 | 6 | 30,204 | Rick Reuschel | Nino Espinosa | Nino Espinosa | Rick Reuschel | | 16 | 34 | -18 |
| 1981-04-20 | @ SLN | 9 | L 1-6 | 1-8 | 6 | 10,454 | Lynn McGlothen | Bob Forsch | Bob Forsch | Lynn McGlothen | Bruce Sutter | 17 | 40 | -23 |
| 1981-04-21 | @ SLN | 10 | L 0-8 | 1-9 | 6 | 11,559 | Ken Kravec | Andy Rincon | Andy Rincon | Ken Kravec | | 17 | 48 | -31 |
| 1981-04-22 | @ SLN | 11 | L 0-3 | 1-10 | 6 | 10,588 | Mike Krukow | Lary Sorensen | Lary Sorensen | Mike Krukow | | 17 | 51 | -34 |
| 1981-04-24 | vs PHI | 12 | L 4-6 | 1-11 | 6 | 6,274 | Rick Reuschel | Steve Carlton | Steve Carlton | Rick Reuschel | Ron Reed | 21 | 57 | -36 |
| 1981-04-25 | vs PHI | 13 | L 5-7 | 1-12 | 6 | 10,990 | Lynn McGlothen | Nino Espinosa | Sparky Lyle | Dick Tidrow | | 26 | 64 | -38 |
| 1981-04-26 | vs PHI | 14 | L 2-6 | 1-13 | 6 | 10,093 | Bill Caudill | Marty Bystrom | Marty Bystrom | Bill Caudill | | 28 | 70 | -42 |
| 1981-04-29 | vs SLN | 15 | W 6-1 | 3-13 | 6 | 0 | Mike Krukow | Andy Rincon | Mike Krukow | Andy Rincon | | 34 | 71 | -37 |
| 1981-04-29 | vs SLN | 16 | W 2-2 | 3-13 | 6 | 4,067 | Lynn McGlothen | Lary Sorensen | | | | 36 | 73 | -37 |
| 1981-05-01 | vs ATL | 17 | L 1-2 | 3-14 | 6 | 2,656 | Bill Caudill | Gaylord Perry | Gaylord Perry | Bill Caudill | | 37 | 75 | -38 |
| 1981-05-02 | vs ATL | 18 | W 5-2 | 4-14 | 6 | 16,936 | Randy Martz | Phil Niekro | Randy Martz | Phil Niekro | Dick Tidrow | 42 | 77 | -35 |
| 1981-05-03 | vs ATL | 19 | L 7-9 | 4-15 | 6 | 10,852 | Lynn McGlothen | John Montefusco | Preston Hanna | Ken Kravec | Rick Camp | 49 | 86 | -37 |
| 1981-05-04 | vs HOU | 20 | L 4-5 | 4-16 | 6 | 2,941 | Mike Krukow | Joaquin Andujar | Joaquin Andujar | Mike Krukow | Joe Sambito | 53 | 91 | -38 |
| 1981-05-05 | vs HOU | 21 | L 3-4 | 4-17 | 6 | 2,092 | Rick Reuschel | Joe Niekro | Dave Smith | Lee Smith | | 56 | 95 | -39 |
| 1981-05-06 | vs HOU | 22 | W 2-1 | 5-17 | 6 | 2,572 | Bill Caudill | Nolan Ryan | Lee Smith | Frank LaCorte | | 58 | 96 | -38 |
| 1981-05-07 | vs HOU | 23 | L 0-6 | 5-18 | 6 | 3,112 | Randy Martz | Bob Knepper | Bob Knepper | Randy Martz | | 58 | 102 | -44 |
| 1981-05-08 | @ ATL | 24 | L 3-4 | 5-19 | 6 | 19,433 | Mike Krukow | John Montefusco | Rick Mahler | Dick Tidrow | | 61 | 106 | -45 |
| 1981-05-09 | @ ATL | 25 | W 7-3 | 6-19 | 6 | 14,365 | Rick Reuschel | Bob Walk | Rick Reuschel | Bob Walk | | 68 | 109 | -41 |
| 1981-05-10 | @ ATL | 26 | L 5-5 | 6-20 | 6 | 9,817 | Bill Caudill | Tommy Boggs | | | | 73 | 114 | -41 |
| 1981-05-12 | @ CIN | 27 | L 1-2 | 6-21 | 6 | 12,016 | Randy Martz | Mario Soto | Mario Soto | Dick Tidrow | | 74 | 116 | -42 |
| 1981-05-13 | @ CIN | 28 | L 3-8 | 6-22 | 6 | 12,528 | Mike Krukow | Tom Seaver | Tom Seaver | Mike Krukow | | 77 | 124 | -47 |
| 1981-05-14 | @ CIN | 29 | L 1-6 | 6-23 | 6 | 11,098 | Rick Reuschel | Bruce Berenyi | Bruce Berenyi | Rick Reuschel | | 78 | 130 | -52 |
| 1981-05-15 | @ HOU | 30 | L 0-5 | 6-24 | 6 | 23,718 | Bill Caudill | Joe Niekro | Joe Niekro | Bill Caudill | | 78 | 135 | -57 |
| 1981-05-16 | @ HOU | 31 | L 1-6 | 6-25 | 6 | 43,726 | Randy Martz | Nolan Ryan | Nolan Ryan | Randy Martz | Joe Sambito | 79 | 141 | -62 |
| 1981-05-17 | @ HOU | 32 | L 1-6 | 6-26 | 6 | 34,068 | Mike Krukow | Bob Knepper | Bob Knepper | Mike Krukow | | 80 | 147 | -67 |
| 1981-05-19 | vs CIN | 33 | L 0-5 | 6-27 | 6 | 5,896 | Rick Reuschel | Tom Seaver | Tom Seaver | Rick Reuschel | Paul Moskau | 80 | 152 | -72 |
| 1981-05-20 | vs CIN | 34 | L 7-10 | 6-28 | 6 | 5,914 | Bill Caudill | Bruce Berenyi | Joe Price | Lee Smith | Tom Hume | 87 | 162 | -75 |
| 1981-05-21 | vs CIN | 35 | W 5-1 | 7-28 | 6 | 7,132 | Randy Martz | Frank Pastore | Randy Martz | Frank Pastore | | 92 | 163 | -71 |
| 1981-05-22 | vs MON | 36 | L 3-6 | 7-29 | 6 | 6,071 | Mike Krukow | Charlie Lea | Charlie Lea | Mike Krukow | | 95 | 169 | -74 |
| 1981-05-23 | vs MON | 37 | W 6-4 | 8-29 | 6 | 15,981 | Rick Reuschel | Ray Burris | Rick Reuschel | Ray Burris | Dick Tidrow | 101 | 173 | -72 |
| 1981-05-24 | vs MON | 38 | W 6-2 | 9-29 | 6 | 10,821 | Bill Caudill | Scott Sanderson | Bill Caudill | Scott Sanderson | Dick Tidrow | 107 | 175 | -68 |
| 1981-05-25 | vs PIT | 39 | W 10-9 | 10-29 | 6 | 18,506 | Randy Martz | Rick Rhoden | Dick Tidrow | Victor Cruz | | 117 | 184 | -67 |
| 1981-05-26 | vs PIT | 40 | L 4-6 | 10-30 | 6 | 6,988 | Mike Krukow | Ernie Camacho | Kent Tekulve | Mike Krukow | Enrique Romo | 121 | 190 | -69 |
| 1981-05-27 | vs PIT | 41 | L 2-3 | 10-31 | 6 | 6,970 | Rick Reuschel | Pascual Perez | Pascual Perez | Rick Reuschel | | 123 | 193 | -70 |
| 1981-05-28 | vs PIT | 42 | L 4-9 | 10-32 | 6 | 7,886 | Bill Caudill | Eddie Solomon | Eddie Solomon | Bill Caudill | | 127 | 202 | -75 |
| 1981-05-29 | @ NYN | 43 | L 1-6 | 10-33 | 6 | 18,035 | Randy Martz | Mike Scott | Mike Scott | Randy Martz | | 128 | 208 | -80 |
| 1981-05-30 | @ NYN | 44 | W 10-3 | 11-33 | 6 | 11,507 | Mike Krukow | Greg Harris | Mike Krukow | Greg Harris | | 138 | 211 | -73 |
| 1981-05-31 | @ NYN | 45 | L 2-3 | 11-34 | 6 | 17,524 | Rick Reuschel | Randy Jones | Randy Jones | Rick Reuschel | Pete Falcone | 140 | 214 | -74 |
| 1981-06-02 | @ PIT | 46 | L 3-16 | 11-35 | 6 | 6,437 | Bill Caudill | Eddie Solomon | Eddie Solomon | Bill Caudill | | 143 | 230 | -87 |
| 1981-06-03 | @ PIT | 47 | L 2-3 | 11-36 | 6 | 5,003 | Randy Martz | Jim Bibby | Jim Bibby | Randy Martz | Enrique Romo | 145 | 233 | -88 |
| 1981-06-04 | @ PIT | 48 | L 4-5 | 11-37 | 6 | 6,740 | Mike Krukow | Rick Rhoden | Kent Tekulve | Lynn McGlothen | | 149 | 238 | -89 |
| 1981-06-05 | vs LAN | 49 | W 4-3 | 12-37 | 6 | 7,815 | Rick Reuschel | Jerry Reuss | Rick Reuschel | Jerry Reuss | Dick Tidrow | 153 | 241 | -88 |
| 1981-06-06 | vs LAN | 50 | W 11-5 | 13-37 | 6 | 30,556 | Bill Caudill | Fernando Valenzuela | Lynn McGlothen | Fernando Valenzuela | | 164 | 246 | -82 |
| 1981-06-07 | vs LAN | 51 | L 0-7 | 13-38 | 6 | 20,024 | Randy Martz | Bob Welch | Bob Welch | Randy Martz | | 164 | 253 | -89 |
| 1981-06-09 | vs SFN | 52 | W 2-1 | 14-38 | 6 | 4,735 | Mike Krukow | Allen Ripley | Mike Krukow | Allen Ripley | Dick Tidrow | 166 | 254 | -88 |
| 1981-06-10 | vs SFN | 53 | W 7-4 | 15-38 | 6 | 6,299 | Rick Reuschel | Doyle Alexander | Rick Reuschel | Doyle Alexander | Dick Tidrow | 173 | 258 | -85 |
| 1981-06-11 | vs SFN | 54 | W 6-1 | 16-38 | 6 | 5,017 | Randy Martz | Tom Griffin | Randy Martz | Tom Griffin | | 179 | 259 | -80 |
| 1981-08-10 | vs NYN | 55 | L 5-7 | 16-39 | 6 | 7,551 | Mike Krukow | Mike Scott | Dyar Miller | Lynn McGlothen | Greg Harris | 184 | 266 | -82 |
| 1981-08-11 | vs NYN | 56 | L 2-4 | 16-40 | 6 | 10,250 | Randy Martz | Pat Zachry | Ray Searage | Lee Smith | Neil Allen | 186 | 270 | -84 |
| 1981-08-12 | vs NYN | 57 | L 4-7 | 16-41 | 6 | 8,372 | Ken Kravec | Ed Lynch | Neil Allen | Dick Tidrow | | 190 | 277 | -87 |
| 1981-08-13 | vs NYN | 58 | W 6-1 | 17-41 | 6 | 7,412 | Doug Bird | Greg Harris | Doug Bird | Greg Harris | Mike Griffin | 196 | 278 | -82 |
| 1981-08-15 | vs PIT | 59 | W 4-3 | 18-41 | 6 | 15,388 | Mike Krukow | Jim Bibby | Randy Martz | Rod Scurry | | 200 | 281 | -81 |
| 1981-08-16 | vs PIT | 60 | L 3-4 | 19-42 | 6 | 0 | Ken Kravec | Rick Rhoden | Kent Tekulve | Lee Smith | Grant Jackson | 203 | 285 | -82 |
| 1981-08-16 | vs PIT | 61 | W 6-4 | 19-42 | 6 | 18,991 | Jay Howell | Pascual Perez | Jay Howell | Pascual Perez | Randy Martz | 209 | 289 | -80 |
| 1981-08-17 | vs LAN | 62 | W 3-1 | 20-42 | 6 | 10,153 | Doug Bird | Bob Welch | Doug Bird | Bob Welch | | 212 | 290 | -78 |
| 1981-08-18 | vs LAN | 63 | L 0-5 | 20-43 | 6 | 15,973 | Mike Griffin | Burt Hooton | Burt Hooton | Mike Griffin | | 212 | 295 | -83 |
| 1981-08-19 | vs LAN | 64 | W 4-3 | 21-43 | 6 | 26,860 | Mike Krukow | Dave Goltz | Mike Krukow | Dave Goltz | Randy Martz | 216 | 298 | -82 |
| 1981-08-21 | vs SFN | 65 | L 3-4 | 21-44 | 6 | 12,826 | Ken Kravec | Tom Griffin | Fred Breining | Dick Tidrow | Greg Minton | 219 | 302 | -83 |
| 1981-08-22 | vs SFN | 66 | L 1-2 | 21-45 | 6 | 16,486 | Doug Bird | Vida Blue | Vida Blue | Doug Bird | Greg Minton | 220 | 304 | -84 |
| 1981-08-23 | vs SFN | 67 | W 6-5 | 22-45 | 6 | 14,737 | Randy Martz | Ed Whitson | Doug Capilla | Gary Lavelle | | 226 | 309 | -83 |
| 1981-08-24 | vs SDN | 68 | W 9-8 | 23-45 | 6 | 7,068 | Mike Krukow | Juan Eichelberger | Lee Smith | Gary Lucas | | 235 | 317 | -82 |
| 1981-08-25 | vs SDN | 69 | W 4-3 | 24-45 | 6 | 5,878 | Ken Kravec | Tim Lollar | Ken Kravec | Tim Lollar | Guillermo Hernandez | 239 | 320 | -81 |
| 1981-08-26 | vs SDN | 70 | W 9-7 | 25-45 | 6 | 9,944 | Doug Bird | Steve Mura | Lee Smith | John Curtis | | 248 | 327 | -79 |
| 1981-08-27 | @ LAN | 71 | L 0-6 | 25-46 | 6 | 48,191 | Randy Martz | Fernando Valenzuela | Fernando Valenzuela | Randy Martz | | 248 | 333 | -85 |
| 1981-08-28 | @ LAN | 72 | L 1-6 | 25-47 | 6 | 42,160 | Mike Krukow | Bob Welch | Bob Welch | Mike Krukow | Dave Stewart | 249 | 339 | -90 |
| 1981-08-29 | @ LAN | 73 | W 3-1 | 26-47 | 6 | 47,424 | Mike Griffin | Burt Hooton | Mike Griffin | Burt Hooton | Lee Smith | 252 | 340 | -88 |
| 1981-08-30 | @ LAN | 74 | W 2-1 | 27-47 | 6 | 34,284 | Doug Bird | Dave Goltz | Doug Bird | Dave Goltz | Dick Tidrow | 254 | 341 | -87 |
| 1981-08-31 | @ SDN | 75 | L 1-4 | 27-48 | 6 | 3,997 | Ken Kravec | Steve Mura | Steve Mura | Ken Kravec | | 255 | 345 | -90 |
| 1981-09-01 | @ SDN | 76 | L 2-3 | 27-49 | 6 | 5,227 | Mike Krukow | Rick Wise | Rick Wise | Mike Krukow | John Urrea | 257 | 348 | -91 |
| 1981-09-02 | @ SDN | 77 | L 4-5 | 27-50 | 6 | 5,099 | Mike Griffin | Chris Welsh | Gary Lucas | Dick Tidrow | | 261 | 353 | -92 |
| 1981-09-03 | @ SFN | 78 | L 0-12 | 27-51 | 6 | 5,573 | Doug Bird | Doyle Alexander | Doyle Alexander | Doug Bird | | 261 | 365 | -104 |
| 1981-09-04 | @ SFN | 79 | L 2-3 | 27-52 | 6 | 9,707 | Randy Martz | Tom Griffin | Al Holland | Dick Tidrow | | 263 | 368 | -105 |
| 1981-09-05 | @ SFN | 80 | W 8-2 | 28-52 | 6 | 9,548 | Mike Krukow | Alan Hargesheimer | Mike Krukow | Alan Hargesheimer | | 271 | 370 | -99 |
| 1981-09-06 | @ SFN | 81 | L 0-3 | 28-53 | 6 | 12,036 | Mike Griffin | Vida Blue | Vida Blue | Mike Griffin | Greg Minton | 271 | 373 | -102 |
| 1981-09-07 | @ SLN | 82 | W 10-0 | 29-53 | 6 | 32,393 | Doug Bird | Lary Sorensen | Doug Bird | Lary Sorensen | | 281 | 373 | -92 |
| 1981-09-08 | @ SLN | 83 | W 4-3 | 30-53 | 6 | 11,341 | Ken Kravec | Silvio Martinez | Dave Geisel | Jim Kaat | Dick Tidrow | 285 | 376 | -91 |
| 1981-09-09 | @ SLN | 84 | W 7-3 | 31-53 | 6 | 13,109 | Mike Krukow | John Martin | Mike Krukow | John Martin | Randy Martz | 292 | 379 | -87 |
| 1981-09-11 | vs MON | 85 | W 6-5 | 32-53 | 6 | 7,204 | Mike Griffin | Ray Burris | Mike Griffin | Ray Burris | Guillermo Hernandez | 298 | 384 | -86 |
| 1981-09-12 | vs MON | 86 | L 0-2 | 32-54 | 6 | 18,124 | Doug Bird | Steve Rogers | Steve Rogers | Doug Bird | Jeff Reardon | 298 | 386 | -88 |
| 1981-09-13 | vs MON | 87 | L 6-10 | 32-55 | 6 | 14,589 | Mike Krukow | Scott Sanderson | Scott Sanderson | Mike Krukow | | 304 | 396 | -92 |
| 1981-09-15 | vs PIT | 88 | L 2-8 | 32-56 | 6 | 5,254 | Mike Griffin | Luis Tiant | Luis Tiant | Mike Griffin | | 306 | 404 | -98 |
| 1981-09-18 | @ MON | 89 | L 0-11 | 32-57 | 6 | 23,606 | Doug Bird | Scott Sanderson | Scott Sanderson | Doug Bird | | 306 | 415 | -109 |
| 1981-09-19 | @ MON | 90 | W 2-1 | 33-57 | 6 | 30,099 | Mike Krukow | Bill Lee | Mike Krukow | Bill Lee | Randy Martz | 308 | 416 | -108 |
| 1981-09-20 | @ MON | 91 | L 0-4 | 33-58 | 6 | 40,851 | Mike Griffin | Bill Gullickson | Bill Gullickson | Mike Griffin | | 308 | 420 | -112 |
| 1981-09-21 | vs SLN | 92 | L 0-2 | 33-59 | 6 | 3,635 | Ken Kravec | Joaquin Andujar | Joaquin Andujar | Ken Kravec | Bruce Sutter | 308 | 422 | -114 |
| 1981-09-22 | vs SLN | 93 | W 4-3 | 34-59 | 6 | 4,531 | Doug Bird | Bob Forsch | Randy Martz | Mark Littell | | 312 | 425 | -113 |
| 1981-09-23 | vs NYN | 94 | W 2-1 | 35-59 | 6 | 2,754 | Mike Krukow | Ed Lynch | Mike Krukow | Ed Lynch | Dick Tidrow | 314 | 426 | -112 |
| 1981-09-24 | vs NYN | 95 | W 10-9 | 36-59 | 6 | 2,555 | Mike Griffin | Pete Falcone | Dick Tidrow | Jesse Orosco | Rawly Eastwick | 324 | 435 | -111 |
| 1981-09-25 | vs PHI | 96 | L 2-9 | 36-60 | 6 | 4,482 | Ken Kravec | Dan Larson | Dan Larson | Ken Kravec | | 326 | 444 | -118 |
| 1981-09-27 | vs PHI | 97 | L 2-5 | 37-61 | 6 | 0 | Doug Bird | Steve Carlton | Steve Carlton | Doug Bird | | 328 | 449 | -121 |
| 1981-09-27 | vs PHI | 98 | W 14-0 | 37-61 | 6 | 18,783 | Mike Krukow | Dick Ruthven | Mike Krukow | Dick Ruthven | | 342 | 449 | -107 |
| 1981-09-28 | @ PIT | 99 | L 0-4 | 38-62 | 6 | 0 | Mike Griffin | Rick Rhoden | Rick Rhoden | Mike Griffin | | 342 | 453 | -111 |
| 1981-09-28 | @ PIT | 100 | W 3-1 | 38-62 | 6 | 3,698 | Dave Geisel | Bob Long | Dave Geisel | Bob Long | Randy Martz | 345 | 454 | -109 |
| 1981-09-29 | @ PIT | 101 | L 6-10 | 38-63 | 6 | 3,439 | Ken Kravec | Odell Jones | Enrique Romo | Dick Tidrow | | 351 | 464 | -113 |
| 1981-09-30 | @ NYN | 102 | L 1-2 | 38-64 | 6 | 4,473 | Doug Bird | Charlie Puleo | Neil Allen | Randy Martz | | 352 | 466 | -114 |
| 1981-10-01 | @ NYN | 103 | L 2-2 | 38-65 | 6 | 3,553 | Mike Krukow | Craig Swan | | | | 354 | 468 | -114 |
| 1981-10-02 | @ PHI | 104 | L 7-9 | 38-66 | 6 | 20,453 | Dave Geisel | Steve Carlton | Ron Reed | Dick Tidrow | | 361 | 477 | -116 |
| 1981-10-03 | @ PHI | 105 | W 8-4 | 39-66 | 6 | 35,169 | Jay Howell | Dickie Noles | Jay Howell | Sparky Lyle | Randy Martz | 369 | 481 | -112 |
| 1981-10-04 | @ PHI | 106 | L 1-2 | 39-67 | 6 | 21,912 | Lee Smith | Mark Davis | Dick Ruthven | Lee Smith | Tug McGraw | 370 | 483 | -113 |