| 8/28/2010 | Virginia-Wise 10 @ Webber International Warriors 30 | |
| 9/4/2010 | Campbell Camels 20 @ Virginia-Wise 16 | |
| 9/11/2010 | Cumberlands KY Patriots 55 @ Virginia-Wise 10 | † |
| 9/18/2010 | Virginia-Wise 10 @ Emory & Henry Wasps 20 | |
| 9/25/2010 | Virginia-Wise 26 @ Union KY Bulldogs 61 | † |
| 10/2/2010 | West Virginia Tech Golden Bears 21 @ Virginia-Wise 56 | † |
| 10/9/2010 | Virginia-Wise 34 @ Kentucky Christian Knights 31 | † |
| 10/23/2010 | Virginia-Wise 33 @ Pikeville Bears 10 | † |
| 10/30/2010 | Virginia-Wise 29 @ Georgetown KY Tigers 58 | † |
| 11/6/2010 | Campbellsville Tigers 45 @ Virginia-Wise 42 | † |
| 11/13/2010 | Lindsey Wilson Blue Raiders 51 @ Virginia-Wise 22 | † |