Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-04 | Abilene Christian | 9 | SMU | 56 | Final | W | 47 |
| 2 | 2021-09-11 | North Texas | 12 | SMU | 35 | Final | W | 23 |
| 3 | 2021-09-18 | SMU | 39 | Louisiana Tech | 37 | Final | W | 2 |
| 4 | 2021-09-25 | SMU | 42 | TCU | 34 | Final | W | 8 |
| 5 | 2021-10-02 | South Florida | 17 | SMU | 41 | Final | W | 24 |
| 6 | 2021-10-09 | SMU | 31 | Navy | 24 | Final | W | 7 |
| 7 | 2021-10-21 | Tulane | 26 | SMU | 55 | Final | W | 29 |
| 8 | 2021-10-30 | SMU | 37 | Houston | 44 | Final | L | -7 |
| 9 | 2021-11-06 | SMU | 25 | Memphis | 28 | Final | L | -3 |
| 10 | 2021-11-13 | Central Florida | 28 | SMU | 55 | Final | W | 27 |
| 11 | 2021-11-20 | SMU | 14 | Cincinnati | 48 | Final | L | -34 |
| 12 | 2021-11-27 | Tulsa (76) | 34 | SMU (45) | 31 | Final | L | -3 |
| 13 | 2021-12-29 | SMU (45) | 0 | Virginia (53) | 0 | Cancelled | - | - |