Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-03 | Michigan State | 38 | Northwestern | 21 | Final | W | 17 |
| 2 | 2021-09-11 | Youngstown State | 14 | Michigan State | 42 | Final | W | 28 |
| 3 | 2021-09-18 | Michigan State | 38 | Miami | 17 | Final | W | 21 |
| 4 | 2021-09-25 | Nebraska | 20 | Michigan State | 23 | Final(OT) | W | 3 |
| 5 | 2021-10-02 | Western Kentucky | 31 | Michigan State | 48 | Final | W | 17 |
| 6 | 2021-10-09 | Michigan State | 31 | Rutgers | 13 | Final | W | 18 |
| 7 | 2021-10-16 | Michigan State | 20 | Indiana | 15 | Final | W | 5 |
| 8 | 2021-10-30 | Michigan | 33 | Michigan State | 37 | Final | W | 4 |
| 9 | 2021-11-06 | Michigan State | 29 | Purdue | 40 | Final | L | -11 |
| 10 | 2021-11-13 | Maryland | 21 | Michigan State | 40 | Final | W | 19 |
| 11 | 2021-11-20 | Michigan State | 7 | Ohio State | 56 | Final | L | -49 |
| 12 | 2021-11-27 | Penn State (28) | 27 | Michigan State (9) | 30 | Final | W | 3 |
| 13 | 2021-12-30 | Pittsburgh (11) | 21 | Michigan State (10) | 31 | Final | W | 10 |