Notre Dame dominated time of possession in the first half but trails Pittsburgh 10-6 at halftime.
The Irish held the ball for 19:26 of the game's first 30 minutes, but was undone by five penalties in the first quarter and a bad goal-line sequence in the second.
Notre Dame carried an 18-play, 89-yard drive between the first and second quarters, and running back Theo Riddick appeared to score on a 2-yard run early in the second.
But the touchdown was overturned on review, and after getting the ball to the 1, Riddick failed on two attempts to score.
He was dropped for a 4-yard on third-and-1, and Kyle Brindza kicked a 20-yard field goal for a 6-3 lead with 10:34 left in the first half.
Pitt made Notre Dame pay for the missed opportunity with 3:55 left in the half as running back Ray Graham stayed on his feet and inbounds to complete a 16-yard touchdown run that gave the Panthers a 10-6 lead.
Notre Dame couldn't respond from there even after Pitt gave the Irish a golden opportunity right before half at midfield.
The Panthers tried to get a first down on fourth-and-1 at the 50 only to have Graham stuffed for no gain.
Tommy Rees, who took over at quarterback after Everett Golson had his helmet knocked off at the end of the previous Irish series, moved Notre Dame to the Pitt 26 with 5 seconds to play.
But Brindza couldn't connect on a 43-yard field goal attempt, pushing it wide right.
Notre Dame ran 43 plays to Pittsburgh's 22, gained 15 first downs and has a 208-160 edge in yards as it trails at half. The Irish didn't commit a penalty in the second quarter after being called for five in the first.
Golson has completed 9 of 15 passes for 88 yards, and Riddick leads the ground game with 52 rushing yards. Nose guard Louis Nix, who is battling the flu, did play in the open half, recording one tackle.
Graham has run for 77 yards, and Pitt quarterback Tino Sunseri has completed 10 of 12 passes for 84 yards.