| 9/11/2010 | Waynesburg Yellow Jackets 35 @ Wilkes 38 | |
| 9/18/2010 | Springfield Pride 44 @ Wilkes 7 | |
| 9/25/2010 | Wilkes 10 @ Utica Pioneers 24 | |
| 10/2/2010 | Albright Lions 35 @ Wilkes 38 | † |
| 10/9/2010 | Wilkes 35 @ Lebanon Valley Flying Dutchmen 28 1OT | † |
| 10/16/2010 | Delaware Valley Aggies 30 @ Wilkes 18 | † |
| 10/23/2010 | Wilkes 28 @ Fairleigh Dickinson-Florham Devils 23 | † |
| 10/30/2010 | Lycoming Warriors 14 @ Wilkes 31 | † |
| 11/6/2010 | Wilkes 21 @ Widener Pride 41 | † |
| 11/13/2010 | King's Monarchs 17 @ Wilkes 21 | † |
| 11/20/2010 | Moravian Greyhounds 26 @ Wilkes 14 (ECAC Southeast Bowl Championship) |