| 1981-04-10 | vs CIN | 1 | W 5-3 | 1-0 | 1 | 34,929 | Tommy Boggs | Mario Soto | Gene Garber | Mario Soto | Rick Camp | 5 | 3 | 2 |
| 1981-04-11 | vs CIN | 2 | L 2-3 | 1-1 | 4 | 15,973 | Gaylord Perry | Mike LaCoss | Doug Bair | Gene Garber | | 7 | 6 | 1 |
| 1981-04-12 | vs CIN | 3 | W 3-2 | 2-1 | 2 | 12,227 | John Montefusco | Frank Pastore | Larry Bradford | Tom Hume | Rick Mahler | 10 | 8 | 2 |
| 1981-04-13 | @ HOU | 4 | W 2-1 | 3-1 | 2 | 34,961 | Phil Niekro | Bob Knepper | Rick Camp | Joe Sambito | Larry Bradford | 12 | 9 | 3 |
| 1981-04-14 | @ HOU | 5 | L 2-8 | 3-2 | 3 | 21,440 | Bob Walk | Joe Niekro | Joe Niekro | Bob Walk | | 14 | 17 | -3 |
| 1981-04-15 | @ HOU | 6 | L 0-2 | 3-3 | 3 | 22,365 | Tommy Boggs | Nolan Ryan | Nolan Ryan | Tommy Boggs | Frank LaCorte | 14 | 19 | -5 |
| 1981-04-17 | vs SFN | 7 | L 2-6 | 3-4 | 3 | 14,028 | Gaylord Perry | Doyle Alexander | Doyle Alexander | Gaylord Perry | | 16 | 25 | -9 |
| 1981-04-18 | vs SFN | 8 | L 1-4 | 3-5 | 4 | 14,260 | John Montefusco | Tom Griffin | Tom Griffin | John Montefusco | | 17 | 29 | -12 |
| 1981-04-19 | vs SFN | 9 | W 4-3 | 4-5 | 3 | 7,443 | Phil Niekro | Allen Ripley | Rick Camp | Greg Minton | | 21 | 32 | -11 |
| 1981-04-21 | @ CIN | 10 | W 10-1 | 5-5 | 2 | 24,022 | Tommy Boggs | Mario Soto | Tommy Boggs | Mario Soto | | 31 | 33 | -2 |
| 1981-04-22 | @ CIN | 11 | W 7-3 | 6-5 | 2 | 15,735 | Gaylord Perry | Mike LaCoss | Gaylord Perry | Mike LaCoss | | 38 | 36 | 2 |
| 1981-04-23 | @ SFN | 12 | W 7-3 | 7-5 | 2 | 4,710 | John Montefusco | Tom Griffin | John Montefusco | Tom Griffin | Rick Camp | 45 | 39 | 6 |
| 1981-04-24 | @ SFN | 13 | W 7-1 | 8-5 | 2 | 6,169 | Bob Walk | Allen Ripley | Bob Walk | Allen Ripley | | 52 | 40 | 12 |
| 1981-04-25 | @ SFN | 14 | W 4-0 | 9-5 | 2 | 6,371 | Phil Niekro | Vida Blue | Phil Niekro | Vida Blue | | 56 | 40 | 16 |
| 1981-04-26 | @ SFN | 15 | L 1-3 | 9-7 | 2 | 0 | Gaylord Perry | Doyle Alexander | Doyle Alexander | Gaylord Perry | Greg Minton | 57 | 43 | 14 |
| 1981-04-26 | @ SFN | 16 | L 5-8 | 9-7 | 2 | 14,144 | Tommy Boggs | Ed Whitson | Al Holland | Tommy Boggs | Gary Lavelle | 62 | 51 | 11 |
| 1981-04-28 | vs HOU | 17 | L 1-2 | 9-8 | 3 | 8,669 | John Montefusco | Don Sutton | Don Sutton | John Montefusco | Dave Smith | 63 | 53 | 10 |
| 1981-04-29 | vs HOU | 18 | L 4-5 | 9-9 | 3 | 8,334 | Bob Walk | Vern Ruhle | Frank LaCorte | Rick Camp | | 67 | 58 | 9 |
| 1981-04-30 | vs HOU | 19 | L 1-5 | 9-10 | 3 | 10,006 | Tommy Boggs | Joe Niekro | Joe Niekro | Tommy Boggs | | 68 | 63 | 5 |
| 1981-05-01 | @ CHN | 20 | W 2-1 | 10-10 | 3 | 2,656 | Gaylord Perry | Bill Caudill | Gaylord Perry | Bill Caudill | | 70 | 64 | 6 |
| 1981-05-02 | @ CHN | 21 | L 2-5 | 10-11 | 3 | 16,936 | Phil Niekro | Randy Martz | Randy Martz | Phil Niekro | Dick Tidrow | 72 | 69 | 3 |
| 1981-05-03 | @ CHN | 22 | W 9-7 | 11-11 | 3 | 10,852 | John Montefusco | Lynn McGlothen | Preston Hanna | Ken Kravec | Rick Camp | 81 | 76 | 5 |
| 1981-05-04 | @ SLN | 23 | W 9-6 | 12-11 | 3 | 9,260 | Bob Walk | Andy Rincon | Larry Bradford | Bruce Sutter | Rick Camp | 90 | 82 | 8 |
| 1981-05-05 | @ SLN | 24 | L 1-4 | 12-12 | 3 | 7,531 | Tommy Boggs | Lary Sorensen | Lary Sorensen | Tommy Boggs | | 91 | 86 | 5 |
| 1981-05-06 | @ SLN | 25 | W 10-2 | 13-12 | 3 | 9,640 | Gaylord Perry | Bob Forsch | Gaylord Perry | Bob Forsch | | 101 | 88 | 13 |
| 1981-05-07 | @ SLN | 26 | W 4-3 | 14-12 | 2 | 13,630 | Phil Niekro | Silvio Martinez | Rick Camp | Silvio Martinez | | 105 | 91 | 14 |
| 1981-05-08 | vs CHN | 27 | W 4-3 | 15-12 | 2 | 19,433 | John Montefusco | Mike Krukow | Rick Mahler | Dick Tidrow | | 109 | 94 | 15 |
| 1981-05-09 | vs CHN | 28 | L 3-7 | 15-13 | 3 | 14,365 | Bob Walk | Rick Reuschel | Rick Reuschel | Bob Walk | | 112 | 101 | 11 |
| 1981-05-10 | vs CHN | 29 | W 5-5 | 16-13 | 2 | 9,817 | Tommy Boggs | Bill Caudill | | | | 117 | 106 | 11 |
| 1981-05-11 | vs PIT | 30 | W 3-2 | 17-13 | 2 | 4,260 | Gaylord Perry | Ernie Camacho | Rick Mahler | Kent Tekulve | | 120 | 108 | 12 |
| 1981-05-12 | vs PIT | 31 | W 2-0 | 18-13 | 2 | 9,711 | Phil Niekro | Eddie Solomon | Phil Niekro | Eddie Solomon | | 122 | 108 | 14 |
| 1981-05-13 | vs PIT | 32 | L 5-7 | 18-14 | 2 | 10,638 | John Montefusco | Jim Bibby | Victor Cruz | Tommy Boggs | Rod Scurry | 127 | 115 | 12 |
| 1981-05-15 | vs SLN | 33 | W 11-3 | 19-14 | 2 | 13,730 | Bob Walk | Lary Sorensen | Preston Hanna | Lary Sorensen | Rick Mahler | 138 | 118 | 20 |
| 1981-05-16 | vs SLN | 34 | L 2-6 | 19-15 | 3 | 21,051 | Tommy Boggs | Silvio Martinez | Silvio Martinez | Tommy Boggs | Bruce Sutter | 140 | 124 | 16 |
| 1981-05-17 | vs SLN | 35 | L 3-4 | 19-16 | 3 | 14,045 | Gaylord Perry | Bob Forsch | Bob Forsch | Gaylord Perry | Bruce Sutter | 143 | 128 | 15 |
| 1981-05-19 | @ PIT | 36 | L 0-5 | 19-17 | 3 | 5,514 | Phil Niekro | Jim Bibby | Jim Bibby | Phil Niekro | | 143 | 133 | 10 |
| 1981-05-20 | @ PIT | 37 | L 1-6 | 19-18 | 3 | 8,351 | Bob Walk | Rick Rhoden | Rick Rhoden | Bob Walk | Enrique Romo | 144 | 139 | 5 |
| 1981-05-22 | vs SDN | 38 | L 2-5 | 19-19 | 4 | 10,752 | Tommy Boggs | Juan Eichelberger | Juan Eichelberger | Tommy Boggs | Gary Lucas | 146 | 144 | 2 |
| 1981-05-23 | vs SDN | 39 | W 7-6 | 20-19 | 3 | 12,453 | Gaylord Perry | Chris Welsh | Rick Camp | Gary Lucas | | 153 | 150 | 3 |
| 1981-05-24 | vs SDN | 40 | L 5-7 | 20-20 | 4 | 19,538 | Phil Niekro | Rick Wise | John Curtis | Phil Niekro | Danny Boone | 158 | 157 | 1 |
| 1981-05-25 | vs LAN | 41 | L 1-7 | 20-21 | 5 | 11,911 | Bob Walk | Burt Hooton | Burt Hooton | Bob Walk | Bobby Castillo | 159 | 164 | -5 |
| 1981-05-27 | vs LAN | 42 | W 3-2 | 21-21 | 4 | 17,581 | Tommy Boggs | Jerry Reuss | Rick Camp | Steve Howe | | 162 | 166 | -4 |
| 1981-05-28 | vs LAN | 43 | W 9-4 | 22-21 | 3 | 26,597 | Gaylord Perry | Fernando Valenzuela | Gaylord Perry | Fernando Valenzuela | | 171 | 170 | 1 |
| 1981-05-29 | @ SDN | 44 | W 7-1 | 23-21 | 3 | 12,214 | Phil Niekro | Rick Wise | Phil Niekro | Rick Wise | Rick Camp | 178 | 171 | 7 |
| 1981-05-30 | @ SDN | 45 | L 1-11 | 23-22 | 3 | 15,217 | Preston Hanna | Steve Mura | Steve Mura | Preston Hanna | | 179 | 182 | -3 |
| 1981-05-31 | @ SDN | 46 | L 1-5 | 23-23 | 3 | 14,138 | Rick Mahler | Juan Eichelberger | Juan Eichelberger | Rick Mahler | | 180 | 187 | -7 |
| 1981-06-01 | @ LAN | 47 | L 2-5 | 23-24 | 5 | 49,136 | Tommy Boggs | Fernando Valenzuela | Fernando Valenzuela | Tommy Boggs | | 182 | 192 | -10 |
| 1981-06-02 | @ LAN | 48 | W 3-1 | 24-24 | 4 | 37,448 | Gaylord Perry | Bob Welch | Gaylord Perry | Dave Stewart | Rick Camp | 185 | 193 | -8 |
| 1981-06-03 | @ LAN | 49 | W 4-2 | 25-24 | 4 | 42,649 | Phil Niekro | Burt Hooton | Phil Niekro | Burt Hooton | Rick Camp | 189 | 195 | -6 |
| 1981-06-05 | vs PHI | 50 | W 4-1 | 26-24 | 3 | 17,059 | Rick Mahler | Steve Carlton | Rick Mahler | Steve Carlton | Rick Camp | 193 | 196 | -3 |
| 1981-06-06 | vs PHI | 51 | L 0-3 | 26-25 | 4 | 15,291 | Tommy Boggs | Larry Christenson | Larry Christenson | Tommy Boggs | Mike Proly | 193 | 199 | -6 |
| 1981-06-07 | vs PHI | 52 | L 5-7 | 26-26 | 4 | 23,482 | Gaylord Perry | Nino Espinosa | Sparky Lyle | Gaylord Perry | Ron Reed | 198 | 206 | -8 |
| 1981-06-09 | @ MON | 53 | L 1-12 | 26-27 | 4 | 28,986 | Phil Niekro | Scott Sanderson | Scott Sanderson | Phil Niekro | | 199 | 218 | -19 |
| 1981-06-10 | @ MON | 54 | L 2-11 | 26-28 | 4 | 24,292 | Rick Mahler | Bill Gullickson | Bill Gullickson | Rick Mahler | | 201 | 229 | -28 |
| 1981-06-11 | @ MON | 55 | L 0-7 | 26-29 | 4 | 25,200 | Tommy Boggs | Steve Rogers | Steve Rogers | Tommy Boggs | | 201 | 236 | -35 |
| 1981-08-10 | @ SDN | 56 | W 3-2 | 27-29 | 4 | 52,608 | Phil Niekro | Juan Eichelberger | Gene Garber | John Urrea | Rick Camp | 204 | 238 | -34 |
| 1981-08-11 | @ SDN | 57 | W 5-1 | 28-29 | 4 | 5,360 | Gaylord Perry | Steve Mura | Gaylord Perry | Steve Mura | | 209 | 239 | -30 |
| 1981-08-12 | @ SDN | 58 | W 4-3 | 29-29 | 3 | 5,094 | Rick Mahler | Rick Wise | Rick Camp | John Curtis | John Montefusco | 213 | 242 | -29 |
| 1981-08-13 | @ LAN | 59 | W 9-1 | 30-29 | 3 | 27,418 | Tommy Boggs | Burt Hooton | Tommy Boggs | Burt Hooton | Gene Garber | 222 | 243 | -21 |
| 1981-08-14 | @ LAN | 60 | L 0-5 | 30-30 | 3 | 35,592 | John Montefusco | Dave Goltz | Dave Goltz | John Montefusco | Alejandro Pena | 222 | 248 | -26 |
| 1981-08-15 | @ LAN | 61 | W 6-4 | 31-30 | 3 | 40,510 | Phil Niekro | Jerry Reuss | Steve Bedrosian | Jerry Reuss | Al Hrabosky | 228 | 252 | -24 |
| 1981-08-16 | @ LAN | 62 | L 5-6 | 31-31 | 4 | 50,340 | Gaylord Perry | Fernando Valenzuela | Tom Niedenfuer | Steve Bedrosian | Dave Stewart | 233 | 258 | -25 |
| 1981-08-18 | vs NYN | 63 | L 0-4 | 31-32 | 4 | 7,566 | Rick Mahler | Ed Lynch | Ed Lynch | Rick Mahler | Neil Allen | 233 | 262 | -29 |
| 1981-08-19 | vs NYN | 64 | W 5-2 | 32-32 | 4 | 6,080 | Tommy Boggs | Mike Scott | Tommy Boggs | Mike Scott | Rick Camp | 238 | 264 | -26 |
| 1981-08-20 | vs NYN | 65 | W 6-4 | 33-32 | 4 | 4,787 | Phil Niekro | Greg Harris | Phil Niekro | Greg Harris | Rick Camp | 244 | 268 | -24 |
| 1981-08-21 | vs MON | 66 | L 1-4 | 33-33 | 4 | 9,103 | Gaylord Perry | Bill Gullickson | Woodie Fryman | Gene Garber | | 245 | 272 | -27 |
| 1981-08-22 | vs MON | 67 | L 4-5 | 34-34 | 4 | 0 | Steve Bedrosian | Ray Burris | Stan Bahnsen | Steve Bedrosian | Jeff Reardon | 249 | 277 | -28 |
| 1981-08-22 | vs MON | 68 | W 9-1 | 34-34 | 4 | 16,185 | John Montefusco | Charlie Lea | John Montefusco | Charlie Lea | Rick Camp | 258 | 278 | -20 |
| 1981-08-23 | vs MON | 69 | W 2-1 | 35-34 | 3 | 10,075 | Rick Mahler | Steve Rogers | Rick Mahler | Steve Rogers | Rick Camp | 260 | 279 | -19 |
| 1981-08-24 | @ PHI | 70 | L 5-7 | 35-35 | 3 | 23,383 | Tommy Boggs | Larry Christenson | Tug McGraw | Al Hrabosky | | 265 | 286 | -21 |
| 1981-08-25 | @ PHI | 71 | W 12-2 | 36-35 | 3 | 33,383 | Phil Niekro | Mark Davis | Phil Niekro | Mark Davis | | 277 | 288 | -11 |
| 1981-08-26 | @ PHI | 72 | W 5-3 | 37-35 | 3 | 28,283 | Gaylord Perry | Dick Ruthven | Rick Camp | Ron Reed | | 282 | 291 | -9 |
| 1981-08-28 | @ MON | 73 | L 0-3 | 37-36 | 3 | 36,474 | Rick Mahler | Steve Rogers | Steve Rogers | Rick Mahler | | 282 | 294 | -12 |
| 1981-08-29 | @ MON | 74 | L 3-4 | 37-37 | 4 | 31,955 | Tommy Boggs | Scott Sanderson | Jeff Reardon | Gene Garber | | 285 | 298 | -13 |
| 1981-08-30 | @ MON | 75 | W 5-4 | 38-37 | 4 | 45,515 | Phil Niekro | Bill Gullickson | Gene Garber | Bill Lee | | 290 | 302 | -12 |
| 1981-08-31 | vs PHI | 76 | L 8-11 | 38-38 | 4 | 8,207 | Gaylord Perry | Dick Ruthven | Dick Ruthven | Gaylord Perry | Ron Reed | 298 | 313 | -15 |
| 1981-09-01 | vs PHI | 77 | L 0-3 | 38-39 | 5 | 3,374 | Rick Mahler | Steve Carlton | Steve Carlton | Rick Mahler | | 298 | 316 | -18 |
| 1981-09-02 | vs PHI | 78 | W 3-2 | 39-39 | 4 | 6,232 | Tommy Boggs | Dickie Noles | Gene Garber | Warren Brusstar | | 301 | 318 | -17 |
| 1981-09-04 | @ NYN | 79 | L 1-4 | 39-40 | 5 | 15,021 | Phil Niekro | Greg Harris | Greg Harris | Phil Niekro | Neil Allen | 302 | 322 | -20 |
| 1981-09-05 | @ NYN | 80 | L 2-4 | 39-41 | 5 | 11,009 | Gaylord Perry | Pat Zachry | Pat Zachry | Gaylord Perry | Neil Allen | 304 | 326 | -22 |
| 1981-09-06 | @ NYN | 81 | W 5-2 | 40-41 | 5 | 19,746 | Rick Mahler | Randy Jones | Rick Mahler | Randy Jones | Gene Garber | 309 | 328 | -19 |
| 1981-09-07 | vs HOU | 82 | L 2-3 | 40-42 | 5 | 7,358 | Tommy Boggs | Bob Knepper | Dave Smith | Rick Camp | Joe Sambito | 311 | 331 | -20 |
| 1981-09-08 | vs HOU | 83 | W 3-2 | 41-42 | 5 | 2,800 | Larry McWilliams | Vern Ruhle | Rick Camp | Billy Smith | | 314 | 333 | -19 |
| 1981-09-09 | vs HOU | 84 | W 9-0 | 42-42 | 4 | 4,482 | Phil Niekro | Nolan Ryan | Phil Niekro | Nolan Ryan | | 323 | 333 | -10 |
| 1981-09-11 | vs SDN | 85 | W 4-1 | 43-42 | 4 | 8,929 | Gaylord Perry | Steve Mura | Gaylord Perry | Steve Mura | Rick Camp | 327 | 334 | -7 |
| 1981-09-12 | vs SDN | 86 | W 5-4 | 44-42 | 4 | 3,950 | Rick Mahler | Steve Fireovid | Rick Camp | Mike Armstrong | | 332 | 338 | -6 |
| 1981-09-13 | vs SDN | 87 | L 4-6 | 44-43 | 4 | 7,625 | Larry McWilliams | Fred Kuhaulua | Gary Lucas | Rick Camp | Eric Show | 336 | 344 | -8 |
| 1981-09-14 | @ SFN | 88 | L 2-4 | 44-44 | 4 | 4,938 | Tommy Boggs | Tom Griffin | Tom Griffin | Tommy Boggs | Greg Minton | 338 | 348 | -10 |
| 1981-09-15 | @ SFN | 89 | L 5-6 | 44-45 | 5 | 3,588 | Phil Niekro | Allen Ripley | Greg Minton | Gene Garber | | 343 | 354 | -11 |
| 1981-09-16 | @ LAN | 90 | L 2-3 | 44-46 | 5 | 19,905 | Gaylord Perry | Jerry Reuss | Jerry Reuss | Gaylord Perry | Steve Howe | 345 | 357 | -12 |
| 1981-09-17 | @ LAN | 91 | L 0-2 | 44-47 | 5 | 46,168 | Rick Mahler | Fernando Valenzuela | Fernando Valenzuela | Rick Mahler | | 345 | 359 | -14 |
| 1981-09-18 | @ SDN | 92 | W 3-0 | 45-47 | 5 | 4,798 | Larry McWilliams | Rick Wise | Larry McWilliams | Rick Wise | | 348 | 359 | -11 |
| 1981-09-19 | @ SDN | 93 | L 3-6 | 45-48 | 5 | 2,906 | Tommy Boggs | Steve Fireovid | Eric Show | Gene Garber | | 351 | 365 | -14 |
| 1981-09-20 | @ SDN | 94 | W 3-1 | 46-48 | 5 | 2,466 | Phil Niekro | Fred Kuhaulua | Al Hrabosky | Steve Mura | Rick Camp | 354 | 366 | -12 |
| 1981-09-22 | @ HOU | 95 | L 0-3 | 46-49 | 5 | 22,564 | Gaylord Perry | Don Sutton | Don Sutton | Gaylord Perry | | 354 | 369 | -15 |
| 1981-09-23 | @ HOU | 96 | W 3-1 | 47-49 | 5 | 24,142 | Rick Mahler | Joe Niekro | Rick Mahler | Joe Niekro | | 357 | 370 | -13 |
| 1981-09-24 | @ HOU | 97 | L 3-5 | 47-50 | 5 | 23,341 | Larry McWilliams | Bob Knepper | Bob Knepper | Larry McWilliams | Dave Smith | 360 | 375 | -15 |
| 1981-09-25 | vs CIN | 98 | L 2-10 | 47-51 | 5 | 7,817 | Tommy Boggs | Mario Soto | Mario Soto | Tommy Boggs | | 362 | 385 | -23 |
| 1981-09-26 | vs CIN | 99 | L 0-2 | 47-52 | 5 | 5,117 | Phil Niekro | Bruce Berenyi | Bruce Berenyi | Phil Niekro | Tom Hume | 362 | 387 | -25 |
| 1981-09-27 | vs CIN | 100 | L 2-4 | 47-53 | 5 | 7,455 | Gaylord Perry | Tom Seaver | Tom Seaver | Gaylord Perry | Mike LaCoss | 364 | 391 | -27 |
| 1981-09-28 | vs LAN | 101 | W 2-1 | 48-53 | 5 | 2,348 | Rick Mahler | Jerry Reuss | Rick Mahler | Jerry Reuss | Rick Camp | 366 | 392 | -26 |
| 1981-09-29 | vs LAN | 102 | L 3-5 | 48-54 | 5 | 2,150 | Tommy Boggs | Bob Welch | Steve Howe | Gene Garber | Dave Stewart | 369 | 397 | -28 |
| 1981-09-30 | vs SFN | 103 | W 9-2 | 49-54 | 5 | 2,724 | Larry McWilliams | Ed Whitson | Larry McWilliams | Ed Whitson | | 378 | 399 | -21 |
| 1981-10-01 | vs SFN | 104 | L 2-6 | 49-55 | 5 | 2,160 | Phil Niekro | Doyle Alexander | Doyle Alexander | Phil Niekro | Greg Minton | 380 | 405 | -25 |
| 1981-10-02 | @ CIN | 105 | W 11-5 | 50-55 | 5 | 14,793 | Gaylord Perry | Frank Pastore | Gaylord Perry | Frank Pastore | | 391 | 410 | -19 |
| 1981-10-03 | @ CIN | 106 | W 4-3 | 51-55 | 5 | 17,544 | Rick Mahler | Tom Seaver | Rick Mahler | Tom Hume | Rick Camp | 395 | 413 | -18 |
| 1981-10-04 | @ CIN | 107 | L 0-3 | 51-56 | 5 | 31,764 | Tommy Boggs | Mario Soto | Mario Soto | Tommy Boggs | | 395 | 416 | -21 |