| 9/2/2010 | Quincy Hawks 7 @ Southern Illinois 70 | |
| 9/11/2010 | Southern Illinois 3 @ Illinois Fighting Illini 35 | |
| 9/18/2010 | SE Missouri State Redhawks 24 @ Southern Illinois 21 | |
| 9/25/2010 | Southern Illinois 28 @ Youngstown State Penguins 31 | † |
| 10/2/2010 | Southern Illinois 38 @ Illinois State Redbirds 17 | † |
| 10/9/2010 | Northern Iowa Panthers 38 @ Southern Illinois 45 | † |
| 10/16/2010 | South Dakota State Jackrabbits 31 @ Southern Illinois 10 | † |
| 10/30/2010 | Southern Illinois 41 @ Missouri State Bears 51 | † |
| 11/6/2010 | Southern Illinois 6 @ North Dakota State Bison 20 | † |
| 11/13/2010 | Western Illinois Leathernecks 10 @ Southern Illinois 20 | † |
| 11/20/2010 | Indiana State Sycamores 21 @ Southern Illinois 49 | † |