| 9/2/2021 | Trine | 52 | at | Manchester | 14 | @ HCA | ||
| 9/3/2021 | Anderson | 7 | at | Hope | 42 | HCA | ||
| 9/4/2021 | Heidelberg | 48 | at | Adrian | 20 | OAC | ||
| Bluffton | 6 | at | Alma | 24 | HCA | |||
| Finlandia | 6 | at | Lawrence | 42 | @ MidW | |||
| Albion | 36 | at | Mt St Joseph | 20 | @ HCA | |||
| Kalamazoo | 24 | at | Oberlin | 17 | @ NCA | |||
| 9/11/2021 | Kalamazoo | 13 | at | Central IA | 69 | @ ARC | ||
| Hope | 21 | at | Coe | 28 | @ ARC | |||
| Albion | 51 | at | Defiance | 0 | @ HCA | |||
| Olivet | 42 | at | Eureka | 23 | @ NAC | |||
| Concordia IL | 26 | at | Finlandia | 2 | NAC | |||
| Adrian | 14 | at | Hanover | 21 | @ HCA | |||
| Alma | 47 | at | Manchester | 23 | @ HCA | |||
| Rose-Hulman | 31 | at | Trine | 30 | HCA | |||
| 9/18/2021 | Greenville | 28 | at | Adrian | 41 | UMWAC | ||
| Hanover | 14 | at | Albion | 24 | HCA | |||
| Anderson | 2 | at | Alma | 51 | HCA | |||
| Rose-Hulman | 20 | at | Hope | 27 | HCA | |||
| Bluffton | 21 | at | Kalamazoo | 20 | HCA | |||
| Manchester | 7 | at | Olivet | 59 | HCA | |||
| Mt St Joseph | 30 | at | Trine | 31 | OT | HCA | ||
| 9/25/2021 | Wisconsin-Eau Claire | 20 | at | Albion | 23 | WIAC | ||
| Trine | 7 | at | Centre | 14 | @ SAA | |||
| Adrian | 56 | at | Finlandia | 6 | ||||
| Northwestern MN | 10 | at | Hope | 52 | UMWAC | |||
| Alfred | 10 | at | Kalamazoo | 7 | E8 | |||
| Alma | 35 | at | Martin Luther | 27 | @ UMWAC | |||
| Olivet | 44 | at | Millsaps | 27 | @ SAA | |||
| 10/2/2021 | Olivet | 33 | at | Alma | 10 | |||
| Kalamazoo | 0 | at | Hope | 67 | ||||
| Finlandia | 13 | at | Northwestern MN | 16 | @ UMWAC | |||
| Adrian | 20 | at | Trine | 36 | ||||
| 10/9/2021 | Albion | 7 | at | Adrian | 21 | |||
| Minnesota-Morris | 41 | at | Finlandia | 20 | UMWAC | |||
| Alma | 28 | at | Kalamazoo | 3 | ||||
| Trine | 35 | at | Olivet | 14 | ||||
| 10/16/2021 | Alma | 21 | at | Adrian | 36 | |||
| Martin Luther | at | Finlandia | Postponed | UMWAC | ||||
| Albion | 49 | at | Kalamazoo | 0 | ||||
| Hope | 31 | at | Olivet | 16 | ||||
| 10/23/2021 | Olivet | 17 | at | Albion | 38 | |||
| Finlandia | 14 | at | Crown | 19 | @ UMWAC | |||
| Adrian | 7 | at | Hope | 19 | ||||
| Kalamazoo | 13 | at | Trine | 47 | ||||
| 10/30/2021 | Trine | 24 | at | Albion | 31 | |||
| Hope | 27 | at | Alma | 3 | ||||
| Kalamazoo | 7 | at | Olivet | 49 | ||||
| Finlandia | 32 | at | Westminster MO | 42 | @ UMWAC | |||
| 11/6/2021 | Olivet | 35 | at | Adrian | 28 | |||
| Trine | 37 | at | Alma | 23 | ||||
| Greenville | 28 | at | Finlandia | 2 | UMWAC | |||
| Albion | 41 | at | Hope | 38 | ||||
| 11/13/2021 | Alma | 7 | at | Albion | 34 | |||
| Adrian | 33 | at | Kalamazoo | 21 | ||||
| Finlandia | 6 | at | Olivet | 79 | ||||
| Hope | 17 | at | Trine | 13 | ||||
| 11/20/2021 | Wisconsin-La Crosse | 58 | at | Albion | 23 | WIAC |