The Bearcats (7-1, 3-0 Big East) hold a half-game advantage over the Louisville Cardinals for first place in the conference.
Zach Collaros threw for 214 yards on 19-of-32 passing, but had two interceptions.
Isaiah Pead carried the ball 22 times for 118 yards, and Collaros ran for two scores.
Anthony McClung had four receptions for 73 yards and Kenbrell Thompkins caught five balls for 39 yards.
Tino Sunseri completed 24-of-38 passes for 218 yards, a touchdown and interception for the Panthers (4-5, 2-2), who've lost three of their last four games.
Sunseri had 64 yards rushing and a touchdown and Zach Brown added 54 yards on 11 carries.
It was Pittsburgh's first game without leading rusher Ray Graham, who tore the ACL in his right knee in last Wednesday's game against Connecticut. Graham ran for 958 yards and nine touchdowns on 164 carries this season.