Senorise Perry rushed for 101 yards and a career-high four touchdowns to help No. 18 Louisville race by Pittsburgh 45-35 on Saturday.
Teddy Bridgewater passed for 304 yards for the Cardinals (6-0, 1-0 Big East), including a 75-yard score to DeVante Parker on the first play of the second half as Louisville continued its best start since 2006.
Parker's score came in the middle of a 24-point burst by Louisville spanning the second and third quarters that turned a seven-point deficit into a 38-21 lead.
Tino Sunseri passed for 287 yards and two touchdowns but Pitt (2-4, 0-3) couldn't complete a late rally.
Trailing by 10 with 5 minutes to play, Pitt went for it on fourth down deep in Louisville territory rather than attempt a field goal. Sunseri's pass was off the mark and Perry finished off the Panthers with a 59-yard sprint down the left sideline.
Louisville began the season as the overwhelming Big East favorite but some of the shine was stripped away by sluggish road wins at overmatched Florida International and Southern Mississippi coupled with the impressive starts by No. 20 Rutgers and No. 21 Cincinnati.
The Cardinals have been parked toward the bottom of the Top 25 all season and were the last Football Bowl Subdivision team in the country to play a conference game.
Louisville took its time getting going against Pitt, but left little doubt after finding its footing. A 27-yard strike from Bridgewater to Parker late in the first half set up a field goal that trimmed Pittsburgh's lead to 21-17 at the break, and Bridgewater and Parker made sure the Cardinals held on to the momentum.
Taking over at the Louisville 25 to start the second half, Bridgewater dropped back and found a streaking Parker down the left sideline. The sophomore receiver hauled it in and beat a pair of defenders to the end zone to give Louisville its first lead.
It didn't take long to grow.
Pitt went three-and-out and Louisville started again at its own 32. Eli Rodgers made a beautiful diving grab for a 29-yard gain on third-and-8 to move the Cardinals into Pitt territory and after a 35-yard strike from Bridgewater to Parker - who finished with four receptions for 153 yards and a score - Perry went over from 2 yards out to make it 31-21.
A botched Pitt punt snap later in the third quarter gave the Cardinals the ball deep in Panthers territory, and Perry went up the middle from a yard out to put Louisville up 17.
The Panthers drew within 10 early in the fourth quarter on a quarterback sneak by Sunseri and drove to the Louisville 22 with 4:59 to go. Rather than attempt a 39-yard field goal to get within a touchdown, Pitt went for it and Sunseri threw incomplete to Cam Saddler.
Four plays later it was over as Perry ripped down the sideline for his fourth trip to the end zone.
Pitt had dominated the Cardinals recently, ripping off four straight victories in the series, including a 21-14 win in Louisville last fall that helped prevent the Cardinals from securing an outright Big East title.
For about 29 minutes on Saturday, it looked as if the Panthers would extend the streak to five before programs go their separate ways when Pitt bolts to the Atlantic Coast Conference next summer.
Playing like the team that upset Virginia Tech last month instead of the one that bumbled its way to a loss at Syracuse last week, Pitt took a 21-14 lead late in the first half behind a spectacular 7-yard touchdown pass from Sunseri to Saddler, a blocked punt by Todd Thomas that ended with the sophomore linebacker falling on it in the end zone and a 2-yard leap by Rushel Shell.
When the Panthers got greedy, however, they got in trouble. Faced with a fourth-and-1 at the Louisville 42 late in the first half, Pitt opted to go for it. Shell was stuffed for a 1-yard loss and Louisville took over.
Three plays generated little and the Cardinals had fourth-and-8 at their own 45 with 22 seconds left. Rather than kick, Louisville gambled and Bridgewater delivered a pretty completion to Parker.
The play gave Louisville enough room for John Wallace to hit a 45-yard field goal just before the gun and provide the Cardinals the kickstart they would need.