Dion Lewis rushed 22 times for 104 yards and a touchdown, and Tino Sunseri rebounded from a poor first half to complete 8-of-9 second half passes for 111 yards and a touchdown pass to Ray Graham.
Pitt won the game despite 11 penalties for a total of 116 yards, including five pass interference calls.
The Panthers opened the game as Dan Hutchins kicked a 36-yard field goal to put Pitt up 3-0. South Florida's Maikon Bonani answered with a 35-yard field goal in the second quarter, tying the score at 3-3. The teams would remain tied at halftime.
Pitt took a 10-3 lead on the 12-yard pass from Sunseri to Graham. The Bulls answered that score with a 45-yard touchdown run off a reverse from Terrence Mitchell, the first touchdown of Mitchell's career. Pitt countered with a 22-yard touchdown run from Dion Lewis, as they took a 17-10 lead with 14:53 remaining on the game.
Dom DeCicco led the team with a career-high 13 tackles, while Myles Caragein and Brandon Lindsey came up with a sack. After committing four pass interference penalties in the game, Antwuan Reed came up with an interception on the game's final play, to clinch the win.