| 9/4/2021 | Maryville | 14 | at | Berry | 20 | @ SAA | ||
| LaGrange | 17 | at | Birmingham-Southern | 42 | @ SAA | |||
| Greensboro | 7 | at | Guilford | 21 | @ ODC | |||
| Wisconsin-Oshkosh | 28 | at | Huntingdon AL | 24 | WIAC | |||
| Methodist | 23 | at | Shenandoah | 28 | @ ODC | |||
| Brevard | 14 | at | Shorter | 38 | @ GSC (D2) | |||
| 9/5/2021 | Emory & Henry | 36 | at | North Carolina Wesleyan | 7 | D2Ind (D2) | ||
| 9/11/2021 | Apprentice | 34 | at | Brevard | 27 | OT | None (Unk?) | |
| Birmingham-Southern | 48 | at | Huntingdon AL | 9 | SAA | |||
| Berry | 34 | at | LaGrange | 21 | SAA | |||
| Centre | 40 | at | Maryville | 21 | SAA | |||
| Guilford | at | Methodist | Postponed | ODC | ||||
| Shenandoah | 30 | at | North Carolina Wesleyan | 21 | ODC | |||
| 9/18/2021 | Averett | 48 | at | Greensboro | 2 | ODC | ||
| Methodist | 38 | at | Maryville | 21 | ||||
| Brevard | 32 | at | North Carolina Wesleyan | 7 | ||||
| LaGrange | 38 | at | Southern Virginia | 34 | @ ODC | |||
| 9/25/2021 | Maryville | 10 | at | Averett | 47 | @ ODC | ||
| Huntingdon AL | 21 | at | Brevard | 14 | ||||
| Gallaudet | 49 | at | Greensboro | 42 | ECFC | |||
| North Carolina Wesleyan | 26 | at | LaGrange | 21 | ||||
| Southern Virginia | 14 | at | Methodist | 37 | ODC | |||
| 10/2/2021 | North Carolina Wesleyan | 17 | at | Averett | 9 | @ ODC | ||
| Brevard | 27 | at | Greensboro | 7 | ||||
| Methodist | 21 | at | Huntingdon AL | 48 | ||||
| Southern Virginia | 17 | at | Maryville | 38 | ODC | |||
| 10/9/2021 | Maryville | 0 | at | Brevard | 31 | |||
| LaGrange | 17 | at | Methodist | 34 | ||||
| Greensboro | 0 | at | North Carolina Wesleyan | 21 | ||||
| Huntingdon AL | 48 | at | Southern Virginia | 20 | @ ODC | |||
| 10/16/2021 | Averett | 25 | at | Huntingdon AL | 30 | ODC | ||
| Brevard | 20 | at | LaGrange | 10 | ||||
| Maryville | 31 | at | North Carolina Wesleyan | 26 | ||||
| Greensboro | 14 | at | Southern Virginia | 31 | @ ODC | |||
| 10/23/2021 | Methodist | 31 | at | Averett | 24 | @ ODC | ||
| Southern Virginia | 3 | at | Brevard | 7 | ODC | |||
| Huntingdon AL | 42 | at | Greensboro | 3 | ||||
| LaGrange | 16 | at | Maryville | 52 | ||||
| 10/30/2021 | North Carolina Wesleyan | 7 | at | Huntingdon AL | 30 | |||
| Greensboro | 14 | at | LaGrange | 29 | ||||
| Brevard | 27 | at | Methodist | 31 | ||||
| 11/6/2021 | LaGrange | 22 | at | Averett | 31 | @ ODC | ||
| Methodist | 40 | at | Greensboro | 14 | ||||
| Maryville | 33 | at | Huntingdon AL | 52 | ||||
| Southern Virginia | 10 | at | North Carolina Wesleyan | 19 | ODC | |||
| 11/13/2021 | Averett | 3 | at | Brevard | 40 | ODC | ||
| Huntingdon AL | 55 | at | LaGrange | 9 | ||||
| Greensboro | 14 | at | Maryville | 49 | ||||
| North Carolina Wesleyan | 7 | at | Methodist | 38 | ||||
| 11/20/2021 | Huntingdon AL | 14 | at | Birmingham-Southern | 24 | @ SAA |