Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-04 | Southern Miss | 7 | South Alabama | 31 | Final | L | -24 |
| 2 | 2021-09-11 | Grambling | 0 | Southern Miss | 37 | Final | W | 37 |
| 3 | 2021-09-18 | Troy | 21 | Southern Miss | 9 | Final | L | -12 |
| 4 | 2021-09-25 | Southern Miss | 14 | Alabama | 63 | Final | L | -49 |
| 5 | 2021-10-02 | Southern Miss | 19 | Rice | 24 | Final | L | -5 |
| 6 | 2021-10-09 | UTEP | 26 | Southern Miss | 13 | Final | L | -13 |
| 7 | 2021-10-16 | UAB | 34 | Southern Miss | 0 | Final | L | -34 |
| 8 | 2021-10-30 | Southern Miss | 10 | Middle Tennessee | 35 | Final | L | -25 |
| 9 | 2021-11-06 | North Texas | 38 | Southern Miss | 14 | Final | L | -24 |
| 10 | 2021-11-13 | Southern Miss | 17 | UTSA | 27 | Final | L | -10 |
| 11 | 2021-11-19 | Southern Miss | 35 | Louisiana Tech | 19 | Final | W | 16 |
| 12 | 2021-11-27 | Florida International (176) | 17 | Southern Miss (145) | 37 | Final | W | 20 |