| 9/3/2021 | Bethany WV | 21 | at | Hiram | 41 | @ NCA | ||
| Carnegie Mellon | 10 | at | Whitworth | 13 | @ NWC | |||
| 9/4/2021 | Thiel | 14 | at | Allegheny | 42 | @ NCA | ||
| Washington & Jefferson | 21 | at | John Carroll | 14 | @ OAC | |||
| Grove City | 39 | at | Juniata | 14 | @ Cen | |||
| Waynesburg | 6 | at | Muskingum | 49 | @ OAC | |||
| Case Western Reserve | 27 | at | Rochester | 20 | @ LL | |||
| Mount Union | 48 | at | Westminster PA | 7 | OAC | |||
| Geneva | 35 | at | Wooster | 42 | @ NCA | |||
| 9/11/2021 | St Vincent | 34 | at | Bluffton | 14 | @ HCA | ||
| Carnegie Mellon | 31 | at | Geneva | 17 | ||||
| Bethany WV | 15 | at | Grove City | 48 | ||||
| Washington & Jefferson | 64 | at | Thiel | 12 | ||||
| Case Western Reserve | 66 | at | Waynesburg | 33 | ||||
| 9/18/2021 | Westminster PA | 34 | at | Case Western Reserve | 12 | |||
| Carnegie Mellon | 6 | at | Grove City | 13 | ||||
| Geneva | 42 | at | St Vincent | 24 | ||||
| Bethany WV | 3 | at | Washington & Jefferson | 28 | ||||
| Thiel | 14 | at | Waynesburg | 52 | ||||
| 9/25/2021 | Geneva | 42 | at | Bethany WV | 7 | |||
| Waynesburg | 3 | at | Carnegie Mellon | 39 | ||||
| Washington & Jefferson | 37 | at | Case Western Reserve | 14 | ||||
| St Vincent | 41 | at | Thiel | 7 | ||||
| Grove City | 32 | at | Westminster PA | 33 | ||||
| 10/2/2021 | Carnegie Mellon | 47 | at | Bethany WV | 7 | |||
| Washington & Jefferson | 24 | at | Geneva | 20 | ||||
| Case Western Reserve | 40 | at | St Vincent | 42 | ||||
| Westminster PA | 49 | at | Thiel | 14 | ||||
| Grove City | 38 | at | Waynesburg | 0 | ||||
| 10/9/2021 | Thiel | 7 | at | Bethany WV | 28 | |||
| Westminster PA | 10 | at | Carnegie Mellon | 34 | ||||
| Geneva | 7 | at | Grove City | 56 | ||||
| St Vincent | 22 | at | Washington & Jefferson | 63 | ||||
| 10/16/2021 | Bethany WV | 0 | at | Case Western Reserve | 53 | |||
| Grove City | 41 | at | St Vincent | 29 | ||||
| Waynesburg | 14 | at | Westminster PA | 66 | ||||
| 10/23/2021 | Thiel | 0 | at | Carnegie Mellon | 53 | |||
| Geneva | 38 | at | Case Western Reserve | 42 | ||||
| Westminster PA | 23 | at | Washington & Jefferson | 18 | ||||
| St Vincent | 38 | at | Waynesburg | 7 | ||||
| 10/30/2021 | Westminster PA | 42 | at | Bethany WV | 6 | |||
| Waynesburg | 3 | at | Geneva | 49 | ||||
| Washington & Jefferson | 28 | at | Grove City | 24 | ||||
| Carnegie Mellon | 34 | at | St Vincent | 7 | ||||
| Case Western Reserve | 30 | at | Thiel | 12 | ||||
| 11/6/2021 | Washington & Jefferson | 11 | at | Carnegie Mellon | 27 | |||
| Grove City | 21 | at | Case Western Reserve | 35 | ||||
| Thiel | 0 | at | Geneva | 49 | ||||
| Bethany WV | 7 | at | Waynesburg | 31 | ||||
| St Vincent | 6 | at | Westminster PA | 41 | ||||
| 11/13/2021 | Case Western Reserve | 6 | at | Carnegie Mellon | 24 | |||
| Bethany WV | 7 | at | St Vincent | 52 | ||||
| Grove City | 56 | at | Thiel | 0 | ||||
| Waynesburg | 0 | at | Washington & Jefferson | 55 | ||||
| Geneva | 6 | at | Westminster PA | 31 | ||||
| 11/20/2021 | Washington & Jefferson | 7 | at | Brockport State | 20 | @ E8 | ||
| St Vincent | 19 | at | Fairleigh Dickinson-Florham | 38 | @ MidAC | |||
| Utica | 7 | at | Grove City | 49 | E8 | |||
| Carnegie Mellon | at | North Central | Cancelled | @ CCIW | ||||
| Hobart | 21 | at | Westminster PA | 3 | LL |