Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-02 | Mississippi Valley State | 0 | Murray State | 35 | Final | W | 35 |
| 2 | 2021-09-11 | Murray State | 7 | Cincinnati | 42 | Final | L | -35 |
| 3 | 2021-09-18 | Murray State | 10 | Bowling Green | 27 | Final | L | -17 |
| 4 | 2021-10-02 | Eastern Illinois | 6 | Murray State | 22 | Final | W | 16 |
| 5 | 2021-10-09 | Murray State | 24 | Tennessee-Martin | 48 | Final | L | -24 |
| 6 | 2021-10-16 | Murray State | 32 | Southeast Missouri State | 31 | Final | W | 1 |
| 7 | 2021-10-23 | Austin Peay | 47 | Murray State | 6 | Final | L | -41 |
| 8 | 2021-10-30 | Murray State | 21 | Tennessee State | 27 | Final | L | -6 |
| 9 | 2021-11-06 | Tennessee Tech | 27 | Murray State | 32 | Final | W | 5 |
| 10 | 2021-11-13 | Southeast Missouri State | 10 | Murray State | 28 | Final | W | 18 |
| 11 | 2021-11-20 | Murray State | 20 | Eastern Illinois | 13 | Final | W | 7 |