The Eagles (2-0) led the Pioneers 21-14 before getting a 38-yard field goal from Adrian Mora on the final play of the first half.
Georgia Southern then scored on its first two possessions of the second half to break the game wide open.
Jonathan Bryant scored on an 11-yard run and Robert Brown followed with a 12-yard run to give the Eagles an insurmountable 38-14 lead.
The Eagles had 530 yards total offense, including 351 on the ground.
J.J. Wilcox gained 97 on only eight carries, and Robert Brown added 70 on 12 attempts.
Laron Scott returned four kickoffs 161 yards for the Eagles and new school record for most kick return yards for a career with 1,439.
Scott now has 1,439 yards. Karl Miller set the old record of 1,386 in 1987-90.
Georgia Southern quarterback Jaybo Shaw hit 6 of 9 passes for 181 yards and rushed for 28 yards on seven carries.
Tusculum quarterback Bo Cordell hit 35 of 52 passes for 321 yards and two TDs. He also threw an interception for the Pioneers (1-1).
Rashaad Carter caught nine passes for 117 yards and a touchdown for Tusculum.