The victory was an NCAA-best 27th straight season-opening triumph for the Cornhuskers (1-0).
Workhorse running back Rex Burkhead ripped off a 57-yard touchdown run in the first quarter before leaving the game with a left knee injury.
Backup Ameer Abdullah entered and finished with 81 rushing yards on 15 carries for Nebraska.
The Golden Eagles (0-1) were led by quarterback Chris Campbell, who went 6-for-11 passing for 69 yards.
Ellis Johnson fell in his head coaching debut for Southern Miss.