| 9/4/2021 | Butler (3-8) | 7 | at | Illinois State | 49 | Pio | ||
| 9/11/2021 | Illinois State | 0 | at | Western Michigan (8-5) | 28 | at MAC | ||
| 9/18/2021 | Illinois State | 31 | at | Eastern Illinois (1-10) | 24 | at OVC | ||
| 9/25/2021 | Illinois State | 17 | at | Southern Illinois (8-5,6-4) | 35 | |||
| 10/2/2021 | Missouri State (8-4,6-2) | 41 | at | Illinois State | 20 | |||
| 10/16/2021 | North Dakota State (14-1,8-1) | 20 | at | Illinois State | 0 | |||
| 10/23/2021 | Illinois State | 20 | at | South Dakota (7-5,5-4) | 14 | |||
| 10/30/2021 | Illinois State | 31 | at | Western Illinois (2-9,2-6) | 38 | |||
| 11/6/2021 | Northern Iowa (6-6,4-4) | 10 | at | Illinois State | 17 | OT | ||
| 11/13/2021 | Illinois State | 7 | at | North Dakota (5-6,3-5) | 14 | |||
| 11/20/2021 | Indiana State (5-6,3-5) | 15 | at | Illinois State | 10 |
| vs Illinois State | vs Other Opponents | Illinois State compared to OOs | |
| Record: | 7-4 | 60-61 | |
| Points Scored: | 22.36 | 26.92 | 4.56 |
| Points Allowed: | 18.36 | 25.74 | -7.38 |
| Margin: | 4.00 | 1.18 | -2.82 |
| Total Points: | 40.72 | 52.66 | -11.94 |