Aaron Gray's two free throws with 2 seconds left followed three missed 3-pointers by the Cardinals, who fell to 0-3 this season against ranked teams.
Gray finished with 10 points and 12 rebounds for the Panthers (14-0, 3-0), one of three unbeaten teams in Division I along with top-ranked Duke (16-0) and No. 2 Florida (16-0). Pittsburgh has opened the season with 14 straight wins for the second time in three years.
Terrence Williams led the Cardinals (13-3, 1-2) with 25 points.
Despite holding Pittsburgh guard Carl Krauser to eight points on 3-of-10 shooting, the Cardinals simply couldn't match Pittsburgh's size and depth.
The Panthers outrebounded Louisville 39-34 and had 13 second-chance points. Five Panthers scored at least eight points while the Cardinals could find little help for Williams.
Louisville guard Taquan Dean played just 12 minutes, bothered by an ankle injury he re-aggravated late in the first half.
His only field goal - an off-balance 3-pointer from 25 feet - pulled the Cardinals within 59-57 with a minute to play.
Pittsburgh's Levon Kendall missed an 18-footer as the shot clock wound down, and Louisville's Juan Palacios got open for two 3-pointers that would have given the Cardinals the lead. He missed the second badly and Krauser grabbed the rebound and was fouled.
Krauser missed both free throws, but Dean's 3-pointer from the top of the key fell off the rim, and Gray grabbed the rebound to keep the Panthers perfect. The Cardinals had struggled in their previous two games against ranked teams, never leading in losses to Kentucky and Villanova. But Louisville managed to grab a 26-25 halftime lead even with their leading scorer struggling. Dean didn't get off a shot in 7 minutes before apparently re-injuring his ankle and hobbling off the court with 4:20 to play in the half. The Panthers, in their first real road test of the season, had their own problems. Krauser missed all five of his shots from the field, and he and Gray both ran into foul trouble. Pittsburgh remained in the game by dominating the glass and getting plenty of production off the bench. Fields and Sam Young combined for 14 points in the half, and the Panthers grabbed nine offensive rebounds to offset 29 percent shooting. Still, Louisville led by as many as eight points thanks to 6-of-6 shooting from 3-point range.