| 9/2/2021 | Findlay | 14 | at | Ferris State | 54 | @ GLIAC | ||
| Frostburg State | 20 | at | Kentucky Wesleyan | 13 | MtnE | |||
| Shepherd | 35 | at | Ohio Dominican | 30 | PSAC | |||
| Walsh | 27 | at | West Liberty | 6 | @ MtnE | |||
| 9/4/2021 | Lake Erie | 31 | at | Clarion | 26 | @ PSAC | ||
| Tiffin | 34 | at | Marian IN | 10 | @ MSFA (NAIA) | |||
| Hillsdale | 10 | at | Michigan Tech | 14 | @ GLIAC | |||
| Ashland | 35 | at | Notre Dame OH | 42 | OT | @ MtnE | ||
| 9/11/2021 | Ferris State | 45 | at | Ashland | 19 | GLIAC | ||
| UNC Pembroke | 28 | at | Findlay | 34 | OT | MtnE | ||
| Lake Erie | 31 | at | Franklin Pierce | 20 | @ NE10 | |||
| Indianapolis | 35 | at | Hillsdale | 31 | GLV | |||
| Kentucky Wesleyan | 26 | at | Kentucky State | 25 | @ SIAC | |||
| Virginia State | 7 | at | Ohio Dominican | 10 | CIAA | |||
| Northwood | 6 | at | Tiffin | 40 | GLIAC | |||
| Davenport | 10 | at | Walsh | 6 | GLIAC | |||
| 9/18/2021 | Tiffin | 20 | at | Indianapolis | 17 | @ GLV | ||
| Kentucky Wesleyan | 34 | at | Lindenwood | 56 | @ MAIAA | |||
| Lake Erie | 17 | at | McKendree | 10 | @ GLV | |||
| Walsh | 17 | at | Quincy | 38 | @ GLV | |||
| Findlay | 62 | at | Southwest Baptist | 41 | @ GLV | |||
| Hillsdale | 24 | at | Truman State | 38 | @ GLV | |||
| Ohio Dominican | 35 | at | William Jewell | 25 | @ GLV | |||
| 9/25/2021 | Quincy | 23 | at | Ashland | 63 | GLV | ||
| Lindenwood | 28 | at | Findlay | 16 | MAIAA | |||
| Missouri S&T | 31 | at | Hillsdale | 38 | GLV | |||
| Ohio Dominican | 19 | at | Indianapolis | 16 | @ GLV | |||
| William Jewell | 21 | at | Kentucky Wesleyan | 41 | GLV | |||
| Southwest Baptist | 28 | at | Lake Erie | 20 | GLV | |||
| Truman State | 38 | at | Tiffin | 35 | GLV | |||
| McKendree | 24 | at | Walsh | 10 | GLV | |||
| 9/30/2021 | Ashland | 35 | at | Walsh | 10 | |||
| 10/2/2021 | Ohio Dominican | 32 | at | Kentucky Wesleyan | 30 | |||
| Findlay | 37 | at | Lake Erie | 10 | ||||
| Hillsdale | 24 | at | Tiffin | 21 | ||||
| 10/9/2021 | Ohio Dominican | 34 | at | Ashland | 24 | |||
| Kentucky Wesleyan | 19 | at | Findlay | 31 | ||||
| Walsh | 3 | at | Hillsdale | 20 | ||||
| Tiffin | 35 | at | Lake Erie | 17 | ||||
| 10/16/2021 | Lake Erie | 33 | at | Hillsdale | 14 | |||
| Findlay | 21 | at | Ohio Dominican | 14 | ||||
| Ashland | 21 | at | Tiffin | 27 | ||||
| Kentucky Wesleyan | 23 | at | Walsh | 13 | ||||
| 10/23/2021 | Lake Erie | 41 | at | Ashland | 42 | |||
| Hillsdale | 34 | at | Findlay | 29 | ||||
| Tiffin | 34 | at | Kentucky Wesleyan | 28 | ||||
| Walsh | 17 | at | Ohio Dominican | 56 | ||||
| 10/30/2021 | Hillsdale | 17 | at | Ashland | 28 | |||
| Kentucky Wesleyan | 28 | at | Lake Erie | 38 | ||||
| Ohio Dominican | 21 | at | Tiffin | 34 | ||||
| Findlay | 49 | at | Walsh | 0 | ||||
| 11/6/2021 | Ashland | 17 | at | Findlay | 20 | |||
| Kentucky Wesleyan | 12 | at | Hillsdale | 31 | ||||
| Lake Erie | 0 | at | Ohio Dominican | 31 | ||||
| Tiffin | 56 | at | Walsh | 16 | ||||
| 11/13/2021 | Tiffin | 21 | at | Findlay | 26 | |||
| Ohio Dominican | 17 | at | Hillsdale | 21 | ||||
| Ashland | 17 | at | Kentucky Wesleyan | 0 | ||||
| Walsh | 24 | at | Lake Erie | 7 | ||||
| 11/20/2021 | Findlay | 31 | at | Shepherd | 38 | @ PSAC | ||
| 12/4/2021 | Truman State | 34 | at | Hillsdale | 17 | GLV |