| 9/2/2021 | Wagner (0-11) | 7 | at | Buffalo | 69 | NE (1AA) | ||
| 9/11/2021 | Buffalo | 3 | at | Nebraska (3-9) | 28 | at B10 | ||
| 9/18/2021 | Coastal Carolina (11-2) | 28 | at | Buffalo | 25 | SBC | ||
| 9/25/2021 | Buffalo | 35 | at | Old Dominion (6-7) | 34 | at CUSA | ||
| 10/2/2021 | Western Michigan (8-5,4-4) | 24 | at | Buffalo | 17 | |||
| 10/9/2021 | Buffalo | 38 | at | Kent State (7-7,6-3) | 48 | |||
| 10/16/2021 | Ohio (3-9,3-5) | 26 | at | Buffalo | 27 | |||
| 10/23/2021 | Buffalo | 45 | at | Akron (2-10,1-7) | 10 | |||
| 10/30/2021 | Bowling Green (4-8,2-6) | 56 | at | Buffalo | 44 | |||
| 11/9/2021 | Buffalo | 18 | at | Miami-Ohio (7-6,5-3) | 45 | |||
| 11/17/2021 | Northern Illinois (9-5,7-2) | 33 | at | Buffalo | 27 | OT | ||
| 11/23/2021 | Buffalo | 3 | at | Ball State (6-7,4-4) | 20 |
| vs Buffalo | vs Other Opponents | Buffalo compared to OOs | |
| Record: | 8-4 | 58-82 | |
| Points Scored: | 29.92 | 27.13 | -2.79 |
| Points Allowed: | 29.25 | 30.06 | -0.81 |
| Margin: | 0.67 | -2.93 | -3.60 |
| Total Points: | 59.17 | 57.19 | 1.98 |