Southern Miss (3-0) trailed until the fourth quarter, with fumbles and penalties allowing the Cavaliers to surge to a 13-0 lead after one quarter.
Virginia (0-3) scored on a 69-yard pass from Jameel Sewell to Tim Smith and had two field goals, thanks to Southern Miss fumbles.
A roughing the passer call on Southern Miss set up 4-yard TD run by Sewell to give the Cavaliers a 27-10 lead at halftime.
The victory is Southern Miss' eighth straight.
Southern Miss is 4-2 in home games against BCS conference opponents since 2001. The last big conference school in town was North Carolina State, which fell 37-17 in 2006.