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 | W | 26 |
| 2 | 2021-09-11 | Southern Illinois | 23 | Kansas State | 31 | Final | L | -8 |
| 3 | 2021-09-18 | Dayton | 3 | Southern Illinois | 55 | Final | W | 52 |
| 4 | 2021-09-25 | Illinois State | 17 | Southern Illinois | 35 | Final | W | 18 |
| 5 | 2021-10-02 | Southern Illinois | 31 | Western Illinois | 30 | Final(OT) | W | 1 |
| 6 | 2021-10-09 | Southern Illinois | 42 | South Dakota State | 41 | Final(OT) | W | 1 |
| 7 | 2021-10-16 | North Dakota | 28 | Southern Illinois | 31 | Final | W | 3 |
| 8 | 2021-10-30 | Southern Illinois | 16 | Northern Iowa | 23 | Final | L | -7 |
| 9 | 2021-11-06 | Missouri State | 38 | Southern Illinois | 28 | Final | L | -10 |
| 10 | 2021-11-13 | Southern Illinois | 47 | Indiana State | 21 | Final | W | 26 |
| 11 | 2021-11-20 | Youngstown State | 35 | Southern Illinois | 18 | Final | L | -17 |
| 12 | 2021-11-27 | Southern Illinois (140) | 22 | South Dakota (144) | 10 | Final | W | 12 |
| 13 | 2021-12-04 | Southern Illinois (139) | 7 | North Dakota State (86) | 38 | Final | L | -31 |