| 9/2/2021 | Western Illinois | 21 | at | Ball State | 31 | MVC (1AA) | ||
| Wagner | 7 | at | Buffalo | 69 | NE (1AA) | |||
| Bowling Green | 6 | at | Tennessee | 38 | @ SEC | |||
| 9/3/2021 | St Francis PA | 15 | at | Eastern Michigan | 35 | NE (1AA) | ||
| 9/4/2021 | Akron | 10 | at | Auburn | 60 | @ SEC | ||
| Miami-Ohio | 14 | at | Cincinnati | 49 | @ AAC | |||
| Northern Illinois | 22 | at | Georgia Tech | 21 | @ ACC | |||
| Western Michigan | 14 | at | Michigan | 47 | @ B10 | |||
| Central Michigan | 24 | at | Missouri | 34 | @ SEC | |||
| Syracuse | 29 | at | Ohio | 9 | ACC | |||
| Kent State | 10 | at | Texas A&M | 41 | @ SEC | |||
| Norfolk State | 10 | at | Toledo | 49 | MEAC (1AA) | |||
| 9/11/2021 | Temple | 45 | at | Akron | 24 | AAC | ||
| South Alabama | 22 | at | Bowling Green | 19 | SBC | |||
| Robert Morris | 0 | at | Central Michigan | 45 | BigS (1AA) | |||
| VMI | 10 | at | Kent State | 60 | SoCon (1AA) | |||
| Miami-Ohio | 26 | at | Minnesota | 31 | @ B10 | |||
| Buffalo | 3 | at | Nebraska | 28 | @ B10 | |||
| Wyoming | 50 | at | Northern Illinois | 43 | MW | |||
| Toledo | 29 | at | Notre Dame | 32 | @ ND | |||
| Duquesne | 28 | at | Ohio | 26 | NE (1AA) | |||
| Ball State | 13 | at | Penn State | 44 | @ B10 | |||
| Illinois State | 0 | at | Western Michigan | 28 | MVC (1AA) | |||
| Eastern Michigan | 7 | at | Wisconsin | 34 | @ B10 | |||
| 9/16/2021 | Ohio | 14 | at | UL Lafayette | 49 | @ SBC | ||
| 9/18/2021 | Bryant | 14 | at | Akron | 35 | NE (1AA) | ||
| Murray State | 10 | at | Bowling Green | 27 | OVC (1AA) | |||
| Coastal Carolina | 28 | at | Buffalo | 25 | SBC | |||
| Kent State | 7 | at | Iowa | 30 | @ B10 | |||
| Central Michigan | 21 | at | LSU | 49 | @ SEC | |||
| Eastern Michigan | 42 | at | Massachusetts | 28 | @ Ind | |||
| LIU | 7 | at | Miami-Ohio | 42 | NE (1AA) | |||
| Northern Illinois | 10 | at | Michigan | 63 | @ B10 | |||
| Western Michigan | 44 | at | Pittsburgh | 41 | @ ACC | |||
| Colorado State | 22 | at | Toledo | 6 | MW | |||
| Ball State | 12 | at | Wyoming | 45 | @ MW | |||
| 9/25/2021 | Miami-Ohio | 10 | at | Army | 23 | @ Ind | ||
| Toledo | 22 | at | Ball State | 12 | ||||
| Florida Intl | 27 | at | Central Michigan | 31 | CUSA | |||
| Texas State | 21 | at | Eastern Michigan | 59 | SBC | |||
| Kent State | 16 | at | Maryland | 37 | @ B10 | |||
| Bowling Green | 14 | at | Minnesota | 10 | @ B10 | |||
| Maine | 14 | at | Northern Illinois | 41 | CAAF (1AA) | |||
| Ohio | 6 | at | Northwestern | 35 | @ B10 | |||
| Akron | 7 | at | Ohio State | 59 | @ B10 | |||
| Buffalo | 35 | at | Old Dominion | 34 | @ CUSA | |||
| San Jose State | 3 | at | Western Michigan | 23 | MW | |||
| 10/2/2021 | Ohio | 34 | at | Akron | 17 | |||
| Army | 16 | at | Ball State | 28 | Ind | |||
| Western Michigan | 24 | at | Buffalo | 17 | ||||
| Bowling Green | 20 | at | Kent State | 27 | ||||
| Toledo | 45 | at | Massachusetts | 7 | @ Ind | |||
| Central Michigan | 17 | at | Miami-Ohio | 28 | ||||
| Eastern Michigan | 20 | at | Northern Illinois | 27 | ||||
| 10/9/2021 | Akron | 35 | at | Bowling Green | 20 | |||
| Miami-Ohio | 12 | at | Eastern Michigan | 13 | ||||
| Buffalo | 38 | at | Kent State | 48 | ||||
| Central Michigan | 30 | at | Ohio | 27 | ||||
| Northern Illinois | 22 | at | Toledo | 20 | ||||
| Ball State | 45 | at | Western Michigan | 20 | ||||
| 10/16/2021 | Ohio | 26 | at | Buffalo | 27 | |||
| Toledo | 23 | at | Central Michigan | 26 | OT | |||
| Ball State | 38 | at | Eastern Michigan | 31 | ||||
| Akron | 21 | at | Miami-Ohio | 34 | ||||
| Bowling Green | 26 | at | Northern Illinois | 34 | ||||
| Kent State | 31 | at | Western Michigan | 64 | ||||
| 10/23/2021 | Buffalo | 45 | at | Akron | 10 | |||
| Miami-Ohio | 24 | at | Ball State | 17 | ||||
| Eastern Michigan | 55 | at | Bowling Green | 24 | ||||
| Northern Illinois | 39 | at | Central Michigan | 38 | ||||
| Kent State | 34 | at | Ohio | 27 | ||||
| Western Michigan | 15 | at | Toledo | 34 | ||||
| 10/30/2021 | Bowling Green | 56 | at | Buffalo | 44 | |||
| 11/2/2021 | Ball State | 31 | at | Akron | 25 | |||
| Miami-Ohio | 33 | at | Ohio | 35 | ||||
| Eastern Michigan | 52 | at | Toledo | 49 | ||||
| 11/3/2021 | Northern Illinois | 47 | at | Kent State | 52 | |||
| Central Michigan | 42 | at | Western Michigan | 30 | ||||
| 11/9/2021 | Ohio | 34 | at | Eastern Michigan | 26 | |||
| Buffalo | 18 | at | Miami-Ohio | 45 | ||||
| Akron | 40 | at | Western Michigan | 45 | ||||
| 11/10/2021 | Toledo | 49 | at | Bowling Green | 17 | |||
| Kent State | 30 | at | Central Michigan | 54 | ||||
| Ball State | 29 | at | Northern Illinois | 30 | ||||
| 11/16/2021 | Western Michigan | 21 | at | Eastern Michigan | 22 | |||
| Bowling Green | 7 | at | Miami-Ohio | 34 | ||||
| Toledo | 35 | at | Ohio | 23 | ||||
| 11/17/2021 | Central Michigan | 37 | at | Ball State | 17 | |||
| Northern Illinois | 33 | at | Buffalo | 27 | OT | |||
| 11/20/2021 | Kent State | 38 | at | Akron | 0 | |||
| 11/23/2021 | Buffalo | 3 | at | Ball State | 20 | |||
| Western Michigan | 42 | at | Northern Illinois | 21 | ||||
| 11/26/2021 | Ohio | 10 | at | Bowling Green | 21 | |||
| Eastern Michigan | 10 | at | Central Michigan | 31 | ||||
| 11/27/2021 | Miami-Ohio | 47 | at | Kent State | 48 | OT | ||
| Akron | 14 | at | Toledo | 49 | ||||
| 12/4/2021 | Kent State | 23 | vs | Northern Illinois | 41 | MAC Championship Detroit MI | ||
| 12/17/2021 | Northern Illinois | 41 | vs | Coastal Carolina | 47 | Tangerine Cure Bowl - Orlando FL | vs SBC | |
| Middle Tenn State | 31 | vs | Toledo | 24 | Bahamas Bowl - Nassau | vs CUSA | ||
| 12/18/2021 | Eastern Michigan | 20 | vs | Liberty | 56 | Lending Tree Bowl - Mobile AL | vs Ind | |
| 12/21/2021 | Kent State | 38 | vs | Wyoming | 52 | Famous Idaho Potato Bowl - Boise ID | vs MW | |
| 12/23/2021 | North Texas | 14 | vs | Miami-Ohio | 27 | Frisco Football Classic - Frisco TX | vs CUSA | |
| 12/25/2021 | Georgia State | 51 | vs | Ball State | 20 | Camelia Bowl - Montgomery AL | vs SBC | |
| 12/27/2021 | Western Michigan | 52 | vs | Nevada | 24 | Quick Lane Bowl - Detroit MI | vs MW | |
| 12/31/2021 | Washington State | 21 | vs | Central Michigan | 24 | Sun Bowl - El Paso TX | vs P12 |