| 1981-04-09 | @ LAN | 1 | L 0-2 | - | | 50,511 | Joe Niekro | Fernando Valenzuela | Fernando Valenzuela | Joe Niekro | | 0 | 2 | -2 |
| 1981-04-11 | @ LAN | 2 | L 4-7 | - | | 51,691 | Don Sutton | Burt Hooton | Burt Hooton | Don Sutton | | 4 | 9 | -5 |
| 1981-04-12 | @ LAN | 3 | L 2-3 | - | | 50,734 | Vern Ruhle | Rick Sutcliffe | Rick Sutcliffe | Vern Ruhle | Steve Howe | 6 | 12 | -6 |
| 1981-04-13 | vs ATL | 4 | L 1-2 | - | | 34,961 | Bob Knepper | Phil Niekro | Rick Camp | Joe Sambito | Larry Bradford | 7 | 14 | -7 |
| 1981-04-14 | vs ATL | 5 | W 8-2 | - | | 21,440 | Joe Niekro | Bob Walk | Joe Niekro | Bob Walk | | 15 | 16 | -1 |
| 1981-04-15 | vs ATL | 6 | W 2-0 | - | | 22,365 | Nolan Ryan | Tommy Boggs | Nolan Ryan | Tommy Boggs | Frank LaCorte | 17 | 16 | 1 |
| 1981-04-17 | vs PIT | 7 | L 3-4 | - | | 39,119 | Don Sutton | Rick Rhoden | Rick Rhoden | Don Sutton | Enrique Romo | 20 | 20 | 0 |
| 1981-04-18 | vs PIT | 8 | L 3-6 | - | | 29,790 | Vern Ruhle | John Candelaria | Grant Jackson | Dave Smith | | 23 | 26 | -3 |
| 1981-04-19 | vs PIT | 9 | L 0-2 | - | | 30,394 | Joe Niekro | Rod Scurry | Rod Scurry | Joe Niekro | Eddie Solomon | 23 | 28 | -5 |
| 1981-04-20 | vs LAN | 10 | L 2-5 | - | | 21,730 | Joaquin Andujar | Burt Hooton | Burt Hooton | Joaquin Andujar | Dave Goltz | 25 | 33 | -8 |
| 1981-04-21 | vs LAN | 11 | W 1-0 | - | | 21,904 | Bob Knepper | Jerry Reuss | Bob Knepper | Jerry Reuss | | 26 | 33 | -7 |
| 1981-04-22 | vs LAN | 12 | L 0-1 | - | | 22,830 | Don Sutton | Fernando Valenzuela | Fernando Valenzuela | Don Sutton | | 26 | 34 | -8 |
| 1981-04-23 | vs CIN | 13 | L 4-5 | - | | 23,173 | Vern Ruhle | Tom Seaver | Joe Price | Dave Smith | Paul Moskau | 30 | 39 | -9 |
| 1981-04-24 | vs CIN | 14 | L 0-3 | - | | 27,087 | Joe Niekro | Frank Pastore | Frank Pastore | Joe Niekro | | 30 | 42 | -12 |
| 1981-04-25 | vs CIN | 15 | L 1-2 | - | | 19,957 | Nolan Ryan | Bruce Berenyi | Bruce Berenyi | Nolan Ryan | Tom Hume | 31 | 44 | -13 |
| 1981-04-26 | vs CIN | 16 | W 1-0 | - | | 23,428 | Bob Knepper | Mario Soto | Bob Knepper | Mario Soto | | 32 | 44 | -12 |
| 1981-04-28 | @ ATL | 17 | W 2-1 | - | | 8,669 | Don Sutton | John Montefusco | Don Sutton | John Montefusco | Dave Smith | 34 | 45 | -11 |
| 1981-04-29 | @ ATL | 18 | W 5-4 | - | | 8,334 | Vern Ruhle | Bob Walk | Frank LaCorte | Rick Camp | | 39 | 49 | -10 |
| 1981-04-30 | @ ATL | 19 | W 5-1 | - | | 10,006 | Joe Niekro | Tommy Boggs | Joe Niekro | Tommy Boggs | | 44 | 50 | -6 |
| 1981-05-01 | @ PIT | 20 | W 5-3 | - | | 7,012 | Nolan Ryan | Rod Scurry | Joe Sambito | Eddie Solomon | | 49 | 53 | -4 |
| 1981-05-02 | @ PIT | 21 | L 4-5 | - | | 21,993 | Bob Knepper | Rick Rhoden | Eddie Solomon | Dave Smith | | 53 | 58 | -5 |
| 1981-05-03 | @ PIT | 22 | W 3-1 | - | | 10,438 | Don Sutton | Jim Bibby | Don Sutton | Jim Bibby | Dave Smith | 56 | 59 | -3 |
| 1981-05-04 | @ CHN | 23 | W 5-4 | - | | 2,941 | Joaquin Andujar | Mike Krukow | Joaquin Andujar | Mike Krukow | Joe Sambito | 61 | 63 | -2 |
| 1981-05-05 | @ CHN | 24 | W 4-3 | - | | 2,092 | Joe Niekro | Rick Reuschel | Dave Smith | Lee Smith | | 65 | 66 | -1 |
| 1981-05-06 | @ CHN | 25 | L 1-2 | - | | 2,572 | Nolan Ryan | Bill Caudill | Lee Smith | Frank LaCorte | | 66 | 68 | -2 |
| 1981-05-07 | @ CHN | 26 | W 6-0 | - | | 3,112 | Bob Knepper | Randy Martz | Bob Knepper | Randy Martz | | 72 | 68 | 4 |
| 1981-05-08 | @ CIN | 27 | L 0-4 | - | | 31,961 | Don Sutton | Tom Seaver | Tom Seaver | Don Sutton | | 72 | 72 | 0 |
| 1981-05-09 | @ CIN | 28 | L 5-9 | - | | 30,860 | Joaquin Andujar | Bruce Berenyi | Bruce Berenyi | Joaquin Andujar | | 77 | 81 | -4 |
| 1981-05-10 | @ CIN | 29 | W 7-5 | - | | 31,903 | Joe Niekro | Frank Pastore | Joe Niekro | Frank Pastore | Frank LaCorte | 84 | 86 | -2 |
| 1981-05-11 | @ CIN | 30 | W 5-0 | - | | 11,795 | Nolan Ryan | Mike LaCoss | Nolan Ryan | Mike LaCoss | | 89 | 86 | 3 |
| 1981-05-12 | vs SLN | 31 | L 2-3 | - | | 20,020 | Bob Knepper | Bob Forsch | Bruce Sutter | Joe Sambito | Jim Kaat | 91 | 89 | 2 |
| 1981-05-13 | vs SLN | 32 | W 3-0 | - | | 21,705 | Don Sutton | Bob Shirley | Don Sutton | Bob Shirley | | 94 | 89 | 5 |
| 1981-05-14 | vs SLN | 33 | L 6-7 | - | | 20,042 | Bobby Sprowl | Bob Sykes | Jim Otten | Joe Sambito | Bruce Sutter | 100 | 96 | 4 |
| 1981-05-15 | vs CHN | 34 | W 5-0 | - | | 23,718 | Joe Niekro | Bill Caudill | Joe Niekro | Bill Caudill | | 105 | 96 | 9 |
| 1981-05-16 | vs CHN | 35 | W 6-1 | - | | 43,726 | Nolan Ryan | Randy Martz | Nolan Ryan | Randy Martz | Joe Sambito | 111 | 97 | 14 |
| 1981-05-17 | vs CHN | 36 | W 6-1 | - | | 34,068 | Bob Knepper | Mike Krukow | Bob Knepper | Mike Krukow | | 117 | 98 | 19 |
| 1981-05-19 | @ SLN | 37 | L 12-15 | - | | 14,585 | Don Sutton | Bob Shirley | Jim Kaat | Bobby Sprowl | | 129 | 113 | 16 |
| 1981-05-20 | @ SLN | 38 | W 4-3 | - | | 19,175 | Joe Niekro | Lary Sorensen | Joe Niekro | Bruce Sutter | Joe Sambito | 133 | 116 | 17 |
| 1981-05-21 | @ SLN | 39 | L 1-3 | - | | 19,823 | Nolan Ryan | John Martin | John Martin | Nolan Ryan | | 134 | 119 | 15 |
| 1981-05-22 | vs SFN | 40 | L 3-6 | - | | 30,377 | Bob Knepper | Doyle Alexander | Greg Minton | Joaquin Andujar | | 137 | 125 | 12 |
| 1981-05-23 | vs SFN | 41 | W 5-3 | - | | 38,586 | Vern Ruhle | Ed Whitson | Frank LaCorte | Ed Whitson | | 142 | 128 | 14 |
| 1981-05-24 | vs SFN | 42 | L 1-2 | - | | 34,922 | Don Sutton | Vida Blue | Vida Blue | Don Sutton | Greg Minton | 143 | 130 | 13 |
| 1981-05-25 | vs SDN | 43 | W 6-3 | - | | 19,025 | Joe Niekro | Steve Mura | Joe Niekro | Steve Mura | Joe Sambito | 149 | 133 | 16 |
| 1981-05-26 | vs SDN | 44 | W 1-0 | - | | 17,709 | Nolan Ryan | Juan Eichelberger | Nolan Ryan | Juan Eichelberger | Joe Sambito | 150 | 133 | 17 |
| 1981-05-27 | vs SDN | 45 | W 1-0 | - | | 21,256 | Bob Knepper | Chris Welsh | Bob Knepper | Chris Welsh | | 151 | 133 | 18 |
| 1981-05-29 | @ SFN | 46 | L 1-3 | - | | 8,397 | Don Sutton | Vida Blue | Vida Blue | Don Sutton | Al Holland | 152 | 136 | 16 |
| 1981-05-30 | @ SFN | 47 | W 9-8 | - | | 8,869 | Joe Niekro | Allen Ripley | Joaquin Andujar | Fred Breining | Vern Ruhle | 161 | 144 | 17 |
| 1981-05-31 | @ SFN | 48 | L 1-6 | - | | 20,626 | Nolan Ryan | Tom Griffin | Tom Griffin | Nolan Ryan | Al Holland | 162 | 150 | 12 |
| 1981-06-02 | @ SDN | 49 | W 2-1 | - | | 9,671 | Bob Knepper | Chris Welsh | Frank LaCorte | Chris Welsh | Joe Sambito | 164 | 151 | 13 |
| 1981-06-03 | @ SDN | 50 | W 6-1 | - | | 10,023 | Don Sutton | Rick Wise | Don Sutton | Rick Wise | | 170 | 152 | 18 |
| 1981-06-04 | @ SDN | 51 | L 5-7 | - | | 12,403 | Joe Niekro | Steve Mura | Steve Mura | Joe Niekro | Gary Lucas | 175 | 159 | 16 |
| 1981-06-05 | vs NYN | 52 | W 3-0 | - | | 28,085 | Nolan Ryan | Randy Jones | Nolan Ryan | Randy Jones | | 178 | 159 | 19 |
| 1981-06-06 | vs NYN | 53 | W 6-2 | - | | 42,478 | Vern Ruhle | Pat Zachry | Vern Ruhle | Pat Zachry | Dave Smith | 184 | 161 | 23 |
| 1981-06-07 | vs NYN | 54 | L 1-3 | - | | 29,873 | Bob Knepper | Mike Scott | Mike Scott | Bob Knepper | Neil Allen | 185 | 164 | 21 |
| 1981-06-08 | @ PHI | 55 | L 3-4 | - | | 31,664 | Don Sutton | Dick Ruthven | Dick Ruthven | Don Sutton | Tug McGraw | 188 | 168 | 20 |
| 1981-06-09 | @ PHI | 56 | L 3-10 | - | | 33,978 | Joe Niekro | Marty Bystrom | Marty Bystrom | Joe Niekro | Ron Reed | 191 | 178 | 13 |
| 1981-06-10 | @ PHI | 57 | L 4-5 | - | | 57,386 | Nolan Ryan | Steve Carlton | Steve Carlton | Frank LaCorte | Tug McGraw | 195 | 183 | 12 |
| 1981-08-10 | @ SFN | 58 | W 6-5 | - | | 11,115 | Don Sutton | Doyle Alexander | Joe Sambito | Fred Breining | Frank LaCorte | 201 | 188 | 13 |
| 1981-08-11 | @ SFN | 59 | L 2-3 | - | | 12,354 | Joe Niekro | Tom Griffin | Tom Griffin | Joe Niekro | Greg Minton | 203 | 191 | 12 |
| 1981-08-12 | @ SFN | 60 | W 5-4 | - | | 8,707 | Vern Ruhle | Vida Blue | Joe Sambito | Al Holland | Billy Smith | 208 | 195 | 13 |
| 1981-08-13 | @ SDN | 61 | L 1-9 | - | | 4,899 | Bob Knepper | Chris Welsh | Chris Welsh | Bob Knepper | | 209 | 204 | 5 |
| 1981-08-14 | @ SDN | 62 | W 5-1 | - | | 8,414 | Nolan Ryan | Tim Lollar | Nolan Ryan | Tim Lollar | | 214 | 205 | 9 |
| 1981-08-15 | @ SDN | 63 | W 5-0 | - | | 5,852 | Don Sutton | Juan Eichelberger | Don Sutton | Juan Eichelberger | | 219 | 205 | 14 |
| 1981-08-16 | @ SDN | 64 | W 3-0 | - | | 5,880 | Joe Niekro | Steve Mura | Joe Niekro | Steve Mura | Dave Smith | 222 | 205 | 17 |
| 1981-08-17 | vs MON | 65 | L 2-6 | - | | 24,203 | Vern Ruhle | Ray Burris | Ray Burris | Vern Ruhle | Woodie Fryman | 224 | 211 | 13 |
| 1981-08-18 | vs MON | 66 | W 4-2 | - | | 23,306 | Bob Knepper | Steve Rogers | Bob Knepper | Steve Rogers | Joe Sambito | 228 | 213 | 15 |
| 1981-08-19 | vs MON | 67 | W 9-1 | - | | 27,169 | Nolan Ryan | Scott Sanderson | Nolan Ryan | Scott Sanderson | Dave Smith | 237 | 214 | 23 |
| 1981-08-21 | @ PHI | 68 | L 4-5 | - | | 31,693 | Don Sutton | Nino Espinosa | Sparky Lyle | Vern Ruhle | Tug McGraw | 241 | 219 | 22 |
| 1981-08-22 | @ PHI | 69 | L 4-8 | - | | 35,199 | Joe Niekro | Dick Ruthven | Dick Ruthven | Joe Niekro | | 245 | 227 | 18 |
| 1981-08-23 | @ PHI | 70 | L 0-6 | - | | 30,630 | Bob Knepper | Steve Carlton | Steve Carlton | Bob Knepper | | 245 | 233 | 12 |
| 1981-08-25 | @ NYN | 71 | L 1-2 | - | | 15,622 | Nolan Ryan | Greg Harris | Mike Marshall | Joe Sambito | | 246 | 235 | 11 |
| 1981-08-26 | @ NYN | 72 | W 9-3 | - | | 16,731 | Don Sutton | Pat Zachry | Don Sutton | Pat Zachry | | 255 | 238 | 17 |
| 1981-08-27 | @ NYN | 73 | L 2-3 | - | | 17,488 | Joe Niekro | Pete Falcone | Mike Marshall | Joe Sambito | Neil Allen | 257 | 241 | 16 |
| 1981-08-28 | vs PHI | 74 | W 3-2 | - | | 29,482 | Bob Knepper | Steve Carlton | Dave Smith | Sparky Lyle | | 260 | 243 | 17 |
| 1981-08-29 | vs PHI | 75 | W 6-1 | - | | 0 | Vern Ruhle | Mark Davis | Vern Ruhle | Mark Davis | | 266 | 244 | 22 |
| 1981-08-29 | vs PHI | 76 | W 2-1 | - | | 33,327 | Billy Smith | Dickie Noles | Billy Smith | Dickie Noles | Frank LaCorte | 268 | 245 | 23 |
| 1981-08-30 | vs PHI | 77 | W 5-4 | - | | 23,102 | Nolan Ryan | Nino Espinosa | Dave Smith | Sparky Lyle | | 273 | 249 | 24 |
| 1981-08-31 | vs NYN | 78 | W 6-1 | - | | 10,669 | Don Sutton | Pat Zachry | Don Sutton | Pat Zachry | | 279 | 250 | 29 |
| 1981-09-01 | vs NYN | 79 | W 3-2 | - | | 16,339 | Joe Niekro | Pete Falcone | Joe Sambito | Mike Marshall | | 282 | 252 | 30 |
| 1981-09-02 | vs NYN | 80 | W 8-0 | - | | 18,938 | Bob Knepper | Mike Scott | Bob Knepper | Mike Scott | | 290 | 252 | 38 |
| 1981-09-03 | @ MON | 81 | W 2-1 | - | | 24,833 | Vern Ruhle | Scott Sanderson | Vern Ruhle | Scott Sanderson | Dave Smith | 292 | 253 | 39 |
| 1981-09-04 | @ MON | 82 | W 5-0 | - | | 32,580 | Nolan Ryan | Bill Gullickson | Nolan Ryan | Bill Gullickson | Joe Sambito | 297 | 253 | 44 |
| 1981-09-05 | @ MON | 83 | L 2-5 | - | | 30,471 | Don Sutton | Ray Burris | Ray Burris | Don Sutton | | 299 | 258 | 41 |
| 1981-09-06 | @ MON | 84 | W 4-3 | - | | 47,193 | Joe Niekro | Bill Lee | Frank LaCorte | Elias Sosa | | 303 | 261 | 42 |
| 1981-09-07 | @ ATL | 85 | W 3-2 | - | | 7,358 | Bob Knepper | Tommy Boggs | Dave Smith | Rick Camp | Joe Sambito | 306 | 263 | 43 |
| 1981-09-08 | @ ATL | 86 | L 2-3 | - | | 2,800 | Vern Ruhle | Larry McWilliams | Rick Camp | Billy Smith | | 308 | 266 | 42 |
| 1981-09-09 | @ ATL | 87 | L 0-9 | - | | 4,482 | Nolan Ryan | Phil Niekro | Phil Niekro | Nolan Ryan | | 308 | 275 | 33 |
| 1981-09-11 | vs SFN | 88 | W 6-0 | - | | 23,677 | Don Sutton | Vida Blue | Don Sutton | Vida Blue | | 314 | 275 | 39 |
| 1981-09-12 | vs SFN | 89 | W 5-2 | - | | 35,867 | Joe Niekro | Ed Whitson | Joe Niekro | Ed Whitson | Dave Smith | 319 | 277 | 42 |
| 1981-09-13 | vs SFN | 90 | W 3-0 | - | | 19,642 | Bob Knepper | Doyle Alexander | Bob Knepper | Doyle Alexander | Frank LaCorte | 322 | 277 | 45 |
| 1981-09-14 | vs CIN | 91 | L 2-4 | - | | 19,742 | Vern Ruhle | Bruce Berenyi | Bruce Berenyi | Vern Ruhle | | 324 | 281 | 43 |
| 1981-09-15 | vs CIN | 92 | L 0-4 | - | | 16,354 | Nolan Ryan | Charlie Leibrandt | Charlie Leibrandt | Nolan Ryan | | 324 | 285 | 39 |
| 1981-09-16 | @ SDN | 93 | W 5-2 | - | | 4,241 | Don Sutton | Tim Lollar | Don Sutton | Tim Lollar | Joe Sambito | 329 | 287 | 42 |
| 1981-09-17 | @ SDN | 94 | W 9-0 | - | | 2,428 | Joe Niekro | Steve Mura | Joe Niekro | Steve Mura | | 338 | 287 | 51 |
| 1981-09-18 | @ SFN | 95 | L 2-5 | - | | 8,183 | Bob Knepper | Doyle Alexander | Doyle Alexander | Bob Knepper | Al Holland | 340 | 292 | 48 |
| 1981-09-19 | @ SFN | 96 | W 8-1 | - | | 11,522 | Vern Ruhle | Tom Griffin | Vern Ruhle | Tom Griffin | | 348 | 293 | 55 |
| 1981-09-20 | @ SFN | 97 | W 7-3 | - | | 16,824 | Nolan Ryan | Gary Lavelle | Nolan Ryan | Gary Lavelle | | 355 | 296 | 59 |
| 1981-09-22 | vs ATL | 98 | W 3-0 | - | | 22,564 | Don Sutton | Gaylord Perry | Don Sutton | Gaylord Perry | | 358 | 296 | 62 |
| 1981-09-23 | vs ATL | 99 | L 1-3 | - | | 24,142 | Joe Niekro | Rick Mahler | Rick Mahler | Joe Niekro | | 359 | 299 | 60 |
| 1981-09-24 | vs ATL | 100 | W 5-3 | - | | 23,341 | Bob Knepper | Larry McWilliams | Bob Knepper | Larry McWilliams | Dave Smith | 364 | 302 | 62 |
| 1981-09-25 | vs LAN | 101 | L 0-3 | - | | 35,481 | Vern Ruhle | Burt Hooton | Burt Hooton | Vern Ruhle | | 364 | 305 | 59 |
| 1981-09-26 | vs LAN | 102 | W 5-0 | - | | 32,115 | Nolan Ryan | Ted Power | Nolan Ryan | Ted Power | | 369 | 305 | 64 |
| 1981-09-27 | vs LAN | 103 | W 4-1 | - | | 41,686 | Don Sutton | Fernando Valenzuela | Don Sutton | Fernando Valenzuela | | 373 | 306 | 67 |
| 1981-09-28 | vs SDN | 104 | W 2-1 | - | | 21,576 | Joe Niekro | Juan Eichelberger | Joe Sambito | Juan Eichelberger | | 375 | 307 | 68 |
| 1981-09-29 | vs SDN | 105 | L 1-2 | - | | 34,732 | Bob Knepper | Rick Wise | Rick Wise | Bob Knepper | Gary Lucas | 376 | 309 | 67 |
| 1981-09-30 | @ CIN | 106 | L 2-5 | - | | 24,394 | Vern Ruhle | Mario Soto | Mario Soto | Vern Ruhle | Tom Hume | 378 | 314 | 64 |
| 1981-10-01 | @ CIN | 107 | W 8-1 | - | | 26,484 | Nolan Ryan | Bruce Berenyi | Nolan Ryan | Bruce Berenyi | | 386 | 315 | 71 |
| 1981-10-02 | @ LAN | 108 | L 1-6 | - | | 46,108 | Don Sutton | Jerry Reuss | Jerry Reuss | Don Sutton | | 387 | 321 | 66 |
| 1981-10-03 | @ LAN | 109 | L 2-7 | - | | 42,272 | Joe Niekro | Bob Welch | Bob Welch | Joe Niekro | | 389 | 328 | 61 |
| 1981-10-04 | @ LAN | 110 | W 5-3 | - | | 47,072 | Bob Knepper | Burt Hooton | Dave Smith | Dave Goltz | | 394 | 331 | 63 |