| 9/2/2021 | Defiance | 7 | at | Capital (2-8) | 41 | at OAC | ||
| 9/11/2021 | Albion (9-2) | 51 | at | Defiance | 0 | MIAA | ||
| 9/25/2021 | Alfred State (6-5) | 35 | at | Defiance | 28 | ECFC | ||
| 10/2/2021 | Rose-Hulman (8-3,7-0) | 63 | at | Defiance | 14 | |||
| 10/9/2021 | Defiance | 0 | at | Manchester (3-7,3-4) | 22 | |||
| 10/16/2021 | Defiance | 0 | at | Hanover (5-5,4-3) | 51 | |||
| 10/23/2021 | Mt St Joseph (6-4,5-2) | 13 | at | Defiance | 14 | |||
| 10/30/2021 | Franklin (6-4,4-3) | 13 | at | Defiance | 7 | |||
| 11/6/2021 | Defiance | 14 | at | Anderson (1-9,1-6) | 42 | |||
| 11/13/2021 | Bluffton (4-6,3-4) | 30 | at | Defiance | 12 |
| vs Defiance | vs Other Opponents | Defiance compared to OOs | |
| Record: | 9-1 | 41-52 | |
| Points Scored: | 36.10 | 23.52 | -12.58 |
| Points Allowed: | 9.60 | 27.95 | -18.35 |
| Margin: | 26.50 | -4.43 | -30.93 |
| Total Points: | 45.70 | 51.47 | -5.77 |