| 9/3/2021 | Michigan State | 38 | at | Northwestern (3-9,1-8) | 21 | |||
| 9/11/2021 | Youngstown State (3-7) | 14 | at | Michigan State | 42 | MVC (1AA) | ||
| 9/18/2021 | Michigan State | 38 | at | Miami-Florida (7-5) | 17 | at ACC | ||
| 9/25/2021 | Nebraska (3-9,1-8) | 20 | at | Michigan State | 23 | OT | ||
| 10/2/2021 | Western Kentucky (9-5) | 31 | at | Michigan State | 48 | CUSA | ||
| 10/9/2021 | Michigan State | 31 | at | Rutgers (5-8,2-7) | 13 | |||
| 10/16/2021 | Michigan State | 20 | at | Indiana (2-10,0-9) | 15 | |||
| 10/30/2021 | Michigan (12-2,9-1) | 33 | at | Michigan State | 37 | |||
| 11/6/2021 | Michigan State | 29 | at | Purdue (9-4,6-3) | 40 | |||
| 11/13/2021 | Maryland (7-6,3-6) | 21 | at | Michigan State | 40 | |||
| 11/20/2021 | Michigan State | 7 | at | Ohio State (11-2,8-1) | 56 | |||
| 11/27/2021 | Penn State (7-6,4-5) | 27 | at | Michigan State | 30 | |||
| 12/30/2021 | Pittsburgh (11-3) | 21 | vs | Michigan State | 31 | Peach Bowl - Atlanta GA | ACC |
| vs Michigan State | vs Other Opponents | Michigan State compared to OOs | |
| Record: | 2-11 | 87-65 | |
| Points Scored: | 25.31 | 30.93 | 5.62 |
| Points Allowed: | 31.85 | 25.19 | 6.66 |
| Margin: | -6.54 | 5.74 | 12.28 |
| Total Points: | 57.16 | 56.12 | 1.04 |