| 8/28/2021 | UTEP | 30 | at | New Mexico State | 3 | @ Ind | ||
| 9/1/2021 | UAB | 31 | vs | Jacksonville State | 0 | Montgomery AL | vs WAC (1AA) | |
| 9/2/2021 | LIU | 10 | at | Florida Intl | 48 | NE (1AA) | ||
| Tennessee-Martin | 21 | at | Western Kentucky | 59 | OVC (1AA) | |||
| 9/3/2021 | Duke | 28 | at | UNC-Charlotte | 31 | ACC | ||
| Old Dominion | 10 | at | Wake Forest | 42 | @ ACC | |||
| 9/4/2021 | Rice | 17 | at | Arkansas | 38 | @ SEC | ||
| Florida Atlantic | 14 | at | Florida | 35 | @ SEC | |||
| Texas-San Antonio | 37 | at | Illinois | 30 | @ B10 | |||
| Monmouth NJ | 15 | at | Middle Tenn State | 50 | BigS (1AA) | |||
| Louisiana Tech | 34 | at | Mississippi State | 35 | @ SEC | |||
| Marshall | 49 | at | Navy | 7 | @ AAC | |||
| Northwestern State | 14 | at | North Texas | 44 | SLC (1AA) | |||
| Southern Miss | 7 | at | South Alabama | 31 | @ SBC | |||
| Bethune-Cookman | 28 | at | UTEP | 38 | SWAC (1AA) | |||
| 9/10/2021 | UTEP | 13 | at | Boise State | 54 | @ MW | ||
| 9/11/2021 | Western Kentucky | 35 | at | Army | 38 | @ Ind | ||
| Georgia Southern | 6 | at | Florida Atlantic | 38 | SBC | |||
| Texas State | 23 | at | Florida Intl | 17 | OT | SBC | ||
| UAB | 7 | at | Georgia | 56 | @ SEC | |||
| Southeastern Louisiana | 42 | at | Louisiana Tech | 45 | SLC (1AA) | |||
| North Carolina Central | 10 | at | Marshall | 44 | MEAC (1AA) | |||
| Hampton | 7 | at | Old Dominion | 47 | BigS (1AA) | |||
| Houston | 44 | at | Rice | 7 | AAC | |||
| North Texas | 12 | at | SMU | 35 | @ AAC | |||
| Grambling | 0 | at | Southern Miss | 37 | SWAC (1AA) | |||
| Lamar | 0 | at | Texas-San Antonio | 54 | WAC (1AA) | |||
| Gardner-Webb | 10 | at | UNC-Charlotte | 38 | BigS (1AA) | |||
| Middle Tenn State | 14 | at | Virginia Tech | 35 | @ ACC | |||
| 9/18/2021 | Fordham | 14 | at | Florida Atlantic | 45 | Pat (1AA) | ||
| UNC-Charlotte | 9 | at | Georgia State | 20 | @ SBC | |||
| Old Dominion | 17 | at | Liberty | 45 | @ Ind | |||
| SMU | 39 | at | Louisiana Tech | 37 | AAC | |||
| East Carolina | 42 | at | Marshall | 38 | AAC | |||
| UAB | 40 | at | North Texas | 6 | ||||
| Troy | 21 | at | Southern Miss | 9 | SBC | |||
| Rice | 0 | at | Texas | 58 | @ B12 | |||
| Florida Intl | 21 | at | Texas Tech | 54 | @ B12 | |||
| Middle Tenn State | 13 | at | Texas-San Antonio | 27 | ||||
| 9/23/2021 | Marshall | 30 | at | Appalachian State | 31 | @ SBC | ||
| 9/24/2021 | Middle Tenn State | 39 | at | UNC-Charlotte | 42 | |||
| 9/25/2021 | Florida Atlantic | 7 | at | Air Force | 31 | @ MW | ||
| Southern Miss | 14 | at | Alabama | 63 | @ SEC | |||
| Florida Intl | 27 | at | Central Michigan | 31 | @ MAC | |||
| North Texas | 17 | at | Louisiana Tech | 24 | ||||
| Texas-San Antonio | 31 | at | Memphis | 28 | @ AAC | |||
| Buffalo | 35 | at | Old Dominion | 34 | MAC | |||
| Texas Southern | 34 | at | Rice | 48 | SWAC (1AA) | |||
| UAB | 28 | at | Tulane | 21 | @ AAC | |||
| New Mexico | 13 | at | UTEP | 20 | MW | |||
| Indiana | 33 | at | Western Kentucky | 31 | B10 | |||
| 10/2/2021 | Liberty | 36 | at | UAB | 12 | Ind | ||
| Florida Intl | 21 | at | Florida Atlantic | 58 | ||||
| UNC-Charlotte | 14 | at | Illinois | 24 | @ B10 | |||
| Western Kentucky | 31 | at | Michigan State | 48 | @ B10 | |||
| Marshall | 28 | at | Middle Tenn State | 34 | ||||
| Louisiana Tech | 27 | at | North Carolina State | 34 | @ ACC | |||
| Southern Miss | 19 | at | Rice | 24 | ||||
| UNLV | 17 | at | Texas-San Antonio | 24 | MW | |||
| Old Dominion | 21 | at | UTEP | 28 | ||||
| 10/8/2021 | UNC-Charlotte | 45 | at | Florida Intl | 33 | |||
| 10/9/2021 | Florida Atlantic | 14 | at | UAB | 31 | |||
| Middle Tenn State | 13 | at | Liberty | 41 | @ Ind | |||
| Old Dominion | 13 | at | Marshall | 20 | OT | |||
| North Texas | 35 | at | Missouri | 48 | @ SEC | |||
| UTEP | 26 | at | Southern Miss | 13 | ||||
| Texas-San Antonio | 52 | at | Western Kentucky | 46 | ||||
| 10/15/2021 | Marshall | 49 | at | North Texas | 21 | |||
| 10/16/2021 | Western Kentucky | 43 | at | Old Dominion | 20 | |||
| UAB | 34 | at | Southern Miss | 0 | ||||
| Rice | 0 | at | Texas-San Antonio | 45 | ||||
| Louisiana Tech | 3 | at | UTEP | 19 | ||||
| 10/21/2021 | Florida Atlantic | 38 | at | UNC-Charlotte | 9 | |||
| 10/22/2021 | Middle Tenn State | 44 | at | Connecticut | 13 | @ Ind | ||
| 10/23/2021 | Rice | 30 | at | UAB | 24 | |||
| Western Kentucky | 34 | at | Florida Intl | 19 | ||||
| Texas-San Antonio | 45 | at | Louisiana Tech | 16 | ||||
| Liberty | 35 | at | North Texas | 26 | Ind | |||
| 10/30/2021 | UTEP | 25 | at | Florida Atlantic | 28 | |||
| Florida Intl | 0 | at | Marshall | 38 | ||||
| Southern Miss | 10 | at | Middle Tenn State | 35 | ||||
| Louisiana Tech | 20 | at | Old Dominion | 23 | ||||
| North Texas | 30 | at | Rice | 24 | OT | |||
| UNC-Charlotte | 13 | at | Western Kentucky | 45 | ||||
| 11/6/2021 | Louisiana Tech | 38 | at | UAB | 52 | |||
| Marshall | 28 | at | Florida Atlantic | 13 | ||||
| Old Dominion | 47 | at | Florida Intl | 24 | ||||
| North Texas | 38 | at | Southern Miss | 14 | ||||
| Rice | 24 | at | UNC-Charlotte | 31 | OT | |||
| Texas-San Antonio | 44 | at | UTEP | 23 | ||||
| Middle Tenn State | 21 | at | Western Kentucky | 48 | ||||
| 11/13/2021 | UNC-Charlotte | 32 | at | Louisiana Tech | 42 | |||
| UAB | 21 | at | Marshall | 14 | ||||
| Florida Intl | 10 | at | Middle Tenn State | 50 | ||||
| UTEP | 17 | at | North Texas | 20 | ||||
| Florida Atlantic | 16 | at | Old Dominion | 30 | ||||
| Western Kentucky | 42 | at | Rice | 21 | ||||
| Southern Miss | 17 | at | Texas-San Antonio | 27 | ||||
| 11/19/2021 | Southern Miss | 35 | at | Louisiana Tech | 19 | |||
| 11/20/2021 | North Texas | 49 | at | Florida Intl | 7 | |||
| Old Dominion | 24 | at | Middle Tenn State | 17 | ||||
| UAB | 31 | at | Texas-San Antonio | 34 | ||||
| Marshall | 49 | at | UNC-Charlotte | 28 | ||||
| Rice | 28 | at | UTEP | 38 | ||||
| Florida Atlantic | 17 | at | Western Kentucky | 52 | ||||
| 11/26/2021 | UTEP | 25 | at | UAB | 42 | |||
| 11/27/2021 | Middle Tenn State | 27 | at | Florida Atlantic | 17 | |||
| Western Kentucky | 53 | at | Marshall | 21 | ||||
| Texas-San Antonio | 23 | at | North Texas | 45 | ||||
| UNC-Charlotte | 34 | at | Old Dominion | 56 | ||||
| Louisiana Tech | 31 | at | Rice | 35 | ||||
| Florida Intl | 17 | at | Southern Miss | 37 | ||||
| 12/3/2021 | Western Kentucky | 41 | at | Texas-San Antonio | 49 | CUSA Championship | ||
| 12/17/2021 | Middle Tenn State | 31 | vs | Toledo | 24 | Bahamas Bowl - Nassau | vs MAC | |
| 12/18/2021 | Western Kentucky | 59 | vs | Appalachian State | 38 | Boca Raton Bowl - Boca Raton | vs SBC | |
| UAB | 31 | vs | BYU | 28 | Independence Bowl - Shreveport LA | vs Ind | ||
| UTEP | 24 | vs | Fresno State | 31 | New Mexico Bowl - Albuquerque NM | vs MW | ||
| UL Lafayette | 36 | vs | Marshall | 21 | New Orleans Bowl - New Orleans LA | vs SBC | ||
| 12/20/2021 | Old Dominion | 17 | vs | Tulsa | 30 | Myrtle Beach Bowl - Conway SC | vs AAC | |
| 12/21/2021 | Texas-San Antonio | 24 | vs | San Diego State | 38 | Frisco Bowl - Frisco TX | vs MW | |
| 12/23/2021 | North Texas | 14 | vs | Miami-Ohio | 27 | Frisco Football Classic - Frisco TX | vs MAC |