Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-02 | Southern Illinois | 47 | Southeast Missouri State | 21 | Final | L | -26 |
| 2 | 2021-09-11 | Southeast Missouri State | 14 | Sam Houston State | 52 | Final | L | -38 |
| 3 | 2021-09-18 | Southeast Missouri State | 28 | Missouri | 59 | Final | L | -31 |
| 4 | 2021-09-25 | Tennessee State | 14 | Southeast Missouri State | 47 | Final | W | 33 |
| 5 | 2021-10-02 | Southeast Missouri State | 17 | Tennessee Tech | 28 | Final | L | -11 |
| 6 | 2021-10-09 | Southeast Missouri State | 30 | Austin Peay | 14 | Final | W | 16 |
| 7 | 2021-10-16 | Murray State | 32 | Southeast Missouri State | 31 | Final | L | -1 |
| 8 | 2021-10-23 | Southeast Missouri State | 30 | Tennessee-Martin | 38 | Final | L | -8 |
| 9 | 2021-10-30 | Eastern Illinois | 15 | Southeast Missouri State | 38 | Final | W | 23 |
| 10 | 2021-11-13 | Southeast Missouri State | 10 | Murray State | 28 | Final | L | -18 |
| 11 | 2021-11-20 | Tennessee-Martin | 14 | Southeast Missouri State | 31 | Final | W | 17 |