| 9/2/2021 | Defiance | 7 | at | Capital | 41 | @ OAC | ||
| Trine | 52 | at | Manchester | 14 | MIAA | |||
| 9/3/2021 | Anderson | 7 | at | Hope | 42 | @ MIAA | ||
| 9/4/2021 | Bluffton | 6 | at | Alma | 24 | @ MIAA | ||
| Hanover | 34 | at | Centre | 56 | @ SAA | |||
| Franklin | 35 | at | Illinois Wesleyan | 21 | @ CCIW | |||
| Albion | 36 | at | Mt St Joseph | 20 | MIAA | |||
| Wabash | 33 | at | Rose-Hulman | 23 | NCA | |||
| 9/11/2021 | Lakeland | 54 | at | Anderson | 41 | NAC | ||
| St Vincent | 34 | at | Bluffton | 14 | TPAC | |||
| Albion | 51 | at | Defiance | 0 | MIAA | |||
| Rhodes | 29 | at | Franklin | 36 | SAA | |||
| Adrian | 14 | at | Hanover | 21 | MIAA | |||
| Alma | 47 | at | Manchester | 23 | MIAA | |||
| Alfred | 14 | at | Mt St Joseph | 33 | E8 | |||
| Rose-Hulman | 31 | at | Trine | 30 | @ MIAA | |||
| 9/18/2021 | Hanover | 14 | at | Albion | 24 | @ MIAA | ||
| Anderson | 2 | at | Alma | 51 | @ MIAA | |||
| Wisconsin-Platteville | 44 | at | Franklin | 19 | WIAC | |||
| Rose-Hulman | 20 | at | Hope | 27 | @ MIAA | |||
| Bluffton | 21 | at | Kalamazoo | 20 | @ MIAA | |||
| Manchester | 7 | at | Olivet | 59 | @ MIAA | |||
| Mt St Joseph | 30 | at | Trine | 31 | OT | @ MIAA | ||
| 9/25/2021 | Alfred State | 35 | at | Defiance | 28 | ECFC | ||
| 10/2/2021 | Mt St Joseph | 45 | at | Bluffton | 27 | |||
| Rose-Hulman | 63 | at | Defiance | 14 | ||||
| Manchester | 27 | at | Franklin | 24 | OT | |||
| Anderson | 0 | at | Hanover | 49 | ||||
| 10/9/2021 | Bluffton | 32 | at | Anderson | 20 | |||
| Defiance | 0 | at | Manchester | 22 | ||||
| Franklin | 14 | at | Mt St Joseph | 28 | ||||
| Hanover | 21 | at | Rose-Hulman | 31 | ||||
| 10/16/2021 | Bluffton | 6 | at | Franklin | 45 | |||
| Defiance | 0 | at | Hanover | 51 | ||||
| Manchester | 0 | at | Mt St Joseph | 28 | ||||
| Anderson | 7 | at | Rose-Hulman | 62 | ||||
| 10/23/2021 | Franklin | 17 | at | Anderson | 0 | |||
| Hanover | 41 | at | Bluffton | 10 | ||||
| Mt St Joseph | 13 | at | Defiance | 14 | ||||
| Rose-Hulman | 57 | at | Manchester | 14 | ||||
| 10/30/2021 | Franklin | 13 | at | Defiance | 7 | |||
| Manchester | 0 | at | Hanover | 33 | ||||
| Anderson | 18 | at | Mt St Joseph | 35 | ||||
| Bluffton | 12 | at | Rose-Hulman | 48 | ||||
| 11/6/2021 | Defiance | 14 | at | Anderson | 42 | |||
| Manchester | 7 | at | Bluffton | 31 | ||||
| Rose-Hulman | 38 | at | Franklin | 14 | ||||
| Hanover | 6 | at | Mt St Joseph | 23 | ||||
| 11/13/2021 | Bluffton | 30 | at | Defiance | 12 | |||
| Franklin | 27 | at | Hanover | 16 | ||||
| Anderson | 0 | at | Manchester | 3 | ||||
| Mt St Joseph | 21 | at | Rose-Hulman | 58 | ||||
| 11/20/2021 | Rose-Hulman | 21 | at | DePauw | 26 | @ NCA |