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 | L | -17 |
| 2 | 2021-09-11 | Indiana State | 6 | Northwestern | 24 | Final | W | 18 |
| 3 | 2021-09-18 | Northwestern | 23 | Duke | 30 | Final | L | -7 |
| 4 | 2021-09-25 | Ohio | 6 | Northwestern | 35 | Final | W | 29 |
| 5 | 2021-10-02 | Northwestern | 7 | Nebraska | 56 | Final | L | -49 |
| 6 | 2021-10-16 | Rutgers | 7 | Northwestern | 21 | Final | W | 14 |
| 7 | 2021-10-23 | Northwestern | 7 | Michigan | 33 | Final | L | -26 |
| 8 | 2021-10-30 | Minnesota | 41 | Northwestern | 14 | Final | L | -27 |
| 9 | 2021-11-06 | Iowa | 17 | Northwestern | 12 | Final | L | -5 |
| 10 | 2021-11-13 | Northwestern | 7 | Wisconsin | 35 | Final | L | -28 |
| 11 | 2021-11-20 | Purdue | 32 | Northwestern | 14 | Final | L | -18 |
| 12 | 2021-11-27 | Northwestern (110) | 14 | Illinois (65) | 47 | Final | L | -33 |