Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-02 | South Florida | 0 | North Carolina State | 45 | Final | L | -45 |
| 2 | 2021-09-11 | Florida | 42 | South Florida | 20 | Final | L | -22 |
| 3 | 2021-09-18 | Florida A&M | 17 | South Florida | 38 | Final | W | 21 |
| 4 | 2021-09-25 | South Florida | 27 | BYU | 35 | Final | L | -8 |
| 5 | 2021-10-02 | South Florida | 17 | SMU | 41 | Final | L | -24 |
| 6 | 2021-10-16 | Tulsa | 32 | South Florida | 31 | Final | L | -1 |
| 7 | 2021-10-23 | Temple | 14 | South Florida | 34 | Final | W | 20 |
| 8 | 2021-10-28 | South Florida | 14 | East Carolina | 29 | Final | L | -15 |
| 9 | 2021-11-06 | Houston | 60 | South Florida | 42 | Final | L | -18 |
| 10 | 2021-11-12 | Cincinnati | 45 | South Florida | 28 | Final | L | -17 |
| 11 | 2021-11-19 | South Florida | 0 | Tulane | 0 | Cancelled | - | - |
| 12 | 2021-11-20 | South Florida | 14 | Tulane | 45 | Final | L | -31 |
| 13 | 2021-11-26 | South Florida (134) | 13 | Central Florida (55) | 17 | Final | L | -4 |