| 8/28/2021 | Alcorn State | 14 | vs | North Carolina Central | 23 | Atlanta GA | vs MEAC | |
| 9/2/2021 | Mississippi Valley State | 0 | at | Murray State | 35 | @ OVC | ||
| 9/4/2021 | South Carolina State | 41 | at | Alabama A&M | 42 | MEAC | ||
| Miles | 13 | at | Alabama State | 14 | OT | SIAC (D2) | ||
| Lane | 16 | at | Ark Pine Bluff | 34 | SIAC (D2) | |||
| Prairie View | 40 | at | Texas Southern | 17 | ||||
| Southern | 3 | at | Troy | 55 | @ SBC (1A) | |||
| Bethune-Cookman | 28 | at | UTEP | 38 | @ CUSA (1A) | |||
| 9/5/2021 | Jackson State | 7 | vs | Florida A&M | 6 | Miami Gardens FL | ||
| Tennessee State | 10 | vs | Grambling | 16 | Canton OH | vs OVC | ||
| 9/11/2021 | Northwestern State | 10 | at | Alcorn State | 13 | SLC | ||
| Alabama State | 0 | at | Auburn | 62 | @ SEC (1A) | |||
| Texas Southern | 7 | at | Baylor | 66 | @ B12 (1A) | |||
| Bethune-Cookman | 14 | at | UCF | 63 | @ AAC (1A) | |||
| Fort Valley State | 7 | at | Florida A&M | 34 | SIAC (D2) | |||
| Prairie View | 9 | at | Incarnate Word | 40 | @ SLC | |||
| Tennessee State | 16 | vs | Jackson State | 38 | Memphis TN | vs OVC | ||
| Grambling | 0 | at | Southern Miss | 37 | @ CUSA (1A) | |||
| Miles | 24 | at | Southern | 41 | SIAC (D2) | |||
| 9/16/2021 | Alabama A&M | 30 | at | Bethune-Cookman | 27 | |||
| 9/18/2021 | Ark Pine Bluff | 23 | at | Central Arkansas | 45 | @ WAC | ||
| Grambling | 0 | at | Houston | 45 | @ AAC (1A) | |||
| Jackson State | 7 | at | UL Monroe | 12 | @ SBC (1A) | |||
| Houston Baptist | 27 | at | Prairie View | 37 | SLC | |||
| Alcorn State | 21 | at | South Alabama | 28 | @ SBC (1A) | |||
| Florida A&M | 17 | at | South Florida | 38 | @ AAC (1A) | |||
| McNeese State | 31 | at | Southern | 24 | SLC | |||
| Mississippi Valley State | 13 | at | Stephen F. Austin | 58 | @ WAC | |||
| 9/23/2021 | Alcorn State | 39 | at | Ark Pine Bluff | 38 | |||
| 9/25/2021 | Tuskegee | 35 | vs | Alabama A&M | 45 | Mobile AL | vs SIAC (D2) | |
| Bethune-Cookman | 24 | at | Alabama State | 38 | ||||
| Delta State | 17 | at | Jackson State | 24 | GSC (D2) | |||
| Grambling | 10 | vs | Prairie View | 24 | Dallas TX | |||
| Texas Southern | 34 | at | Rice | 48 | @ CUSA (1A) | |||
| 9/26/2021 | Southern | 38 | vs | Mississippi Valley State | 25 | Jackson MS | ||
| 9/30/2021 | Ark Pine Bluff | 17 | at | Prairie View | 27 | |||
| 10/2/2021 | Alabama State | 0 | at | Florida A&M | 28 | |||
| Alabama A&M | 28 | at | Grambling | 37 | ||||
| North Carolina Central | 16 | at | Mississippi Valley State | 17 | MEAC | |||
| Bethune-Cookman | 35 | at | South Carolina State | 42 | @ MEAC | |||
| North American U | 0 | at | Texas Southern | 69 | None (Unk?) | |||
| 10/9/2021 | Jackson State | 61 | at | Alabama A&M | 15 | |||
| Ark Pine Bluff | 15 | at | Alabama State | 35 | ||||
| Grambling | 20 | at | Alcorn State | 24 | ||||
| Mississippi Valley State | 20 | at | Bethune-Cookman | 14 | ||||
| South Carolina State | 7 | at | Florida A&M | 30 | MEAC | |||
| Texas Southern | 35 | vs | Southern | 31 | Arlington TX | |||
| 10/16/2021 | Florida A&M | 35 | at | Alabama A&M | 31 | |||
| Southern | 34 | at | Ark Pine Bluff | 7 | ||||
| Prairie View | 35 | at | Bethune-Cookman | 29 | ||||
| Texas Southern | 20 | at | Grambling | 34 | ||||
| Alabama State | 7 | at | Jackson State | 28 | ||||
| Alcorn State | 24 | at | Mississippi Valley State | 12 | ||||
| 10/23/2021 | Ark Pine Bluff | 3 | vs | Arkansas | 45 | Little Rock AR | vs SEC (1A) | |
| Bethune-Cookman | 12 | at | Jackson State | 42 | ||||
| Florida A&M | 31 | at | Mississippi Valley State | 28 | ||||
| Prairie View | 48 | at | Southern | 21 | ||||
| Alcorn State | 44 | at | Texas Southern | 27 | ||||
| 10/30/2021 | Alabama A&M | 42 | vs | Alabama State | 28 | Birmingham AL | ||
| Grambling | 3 | at | Florida A&M | 26 | ||||
| Jackson State | 28 | at | Mississippi Valley State | 19 | ||||
| Alcorn State | 35 | at | Southern | 38 | ||||
| Ark Pine Bluff | 17 | at | Texas Southern | 59 | ||||
| 11/6/2021 | Mississippi Valley State | 14 | at | Alabama A&M | 42 | |||
| Grambling | 26 | at | Ark Pine Bluff | 33 | ||||
| Alcorn State | 31 | at | Bethune-Cookman | 35 | ||||
| Texas Southern | 21 | at | Jackson State | 41 | ||||
| Alabama State | 20 | at | Prairie View | 24 | ||||
| Florida A&M | 29 | at | Southern | 17 | ||||
| 11/13/2021 | Prairie View | 29 | at | Alcorn State | 31 | |||
| Florida A&M | 37 | at | Ark Pine Bluff | 7 | ||||
| Bethune-Cookman | 31 | at | Grambling | 14 | ||||
| Alabama State | 31 | at | Mississippi Valley State | 44 | ||||
| Jackson State | 21 | at | Southern | 17 | ||||
| Alabama A&M | 52 | at | Texas Southern | 49 | ||||
| 11/20/2021 | Ark Pine Bluff | 24 | at | Alabama A&M | 52 | |||
| Texas Southern | 21 | at | Alabama State | 24 | ||||
| Bethune-Cookman | 21 | vs | Florida A&M | 46 | Orlando FL | |||
| Alcorn State | 10 | at | Jackson State | 24 | ||||
| Prairie View | 3 | at | Texas A&M | 52 | @ SEC (1A) | |||
| 11/25/2021 | Tuskegee | 9 | at | Alabama State | 43 | SIAC (D2) | ||
| 11/27/2021 | Southern | 26 | vs | Grambling | 29 | New Orleans LA | ||
| Mississippi Valley State | 24 | at | Prairie View | 19 | ||||
| Florida A&M | 14 | at | Southeastern Louisiana | 38 | @ SLC | |||
| 12/4/2021 | Prairie View | 10 | at | Jackson State | 27 | SWAC Championship | ||
| 12/18/2021 | South Carolina State | 31 | vs | Jackson State | 10 | Celebration Bowl - Atlanta GA | vs MEAC |