| 9/4/2021 | Abilene Christian (5-6) | 9 | at | SMU | 56 | WAC (1AA) | ||
| 9/11/2021 | North Texas (6-7) | 12 | at | SMU | 35 | CUSA | ||
| 9/18/2021 | SMU | 39 | at | Louisiana Tech (3-9) | 37 | at CUSA | ||
| 9/25/2021 | SMU | 42 | at | TCU (5-7) | 34 | at B12 | ||
| 10/2/2021 | South Florida (2-10,1-7) | 17 | at | SMU | 41 | |||
| 10/9/2021 | SMU | 31 | at | Navy (4-8,3-5) | 24 | |||
| 10/21/2021 | Tulane (2-10,1-7) | 26 | at | SMU | 55 | |||
| 10/30/2021 | SMU | 37 | at | Houston (12-2,8-1) | 44 | |||
| 11/6/2021 | SMU | 25 | at | Memphis (6-6,3-5) | 28 | |||
| 11/13/2021 | UCF (9-4,5-3) | 28 | at | SMU | 55 | |||
| 11/20/2021 | SMU | 14 | at | Cincinnati (13-1,9-0) | 48 | |||
| 11/27/2021 | Tulsa (7-6,5-3) | 34 | at | SMU | 31 | |||
| 12/29/2021 | SMU | vs | Virginia (6-6) | Cancelled Wasabi Fenway Bowl - Boston MA | vs ACC |
| vs SMU | vs Other Opponents | SMU compared to OOs | |
| Record: | 4-8 | 76-74 | |
| Points Scored: | 28.42 | 29.39 | 0.97 |
| Points Allowed: | 38.42 | 27.24 | 11.18 |
| Margin: | -10.00 | 2.15 | 12.15 |
| Total Points: | 66.84 | 56.63 | 10.21 |