South Florida put Notre Dame on its heels after the first quarter, taking a 13-0 lead.
Notre Dame looked to be rolling on its first drive.
The Irish cruised from their 20-yard line to the Bulls' 1 on seven plays with Cierre Wood turning a swing pass into a 31-yard gain and Michael Floyd recording a 26-yard reception.
But on 3rd-and-goal from the 1, backup running back Jonas Gray fumbled and South Florida's Kayvon Webster returned the ball 96 yards for a touchdown and a 7-0 lead with 11 minutes left.
South Florida added a 49-yard field goal from Maikon Bonani just more than six minutes later for a 10-0 lead.
And the Bulls went up 13-0 with 1:08 left after another Bonani field goal, this one from 17 yards. Notre Dame's defense averted a crushing field goal after South Florida got to the Irish 6-yard line because of two face mask penalties by safety Harrison Smith.