Syracuse (24-0, 11-0 ACC) and Wichita State are the lone undefeated teams in Division I.
With the Orange down by one with 4.4 seconds left, Ennis caught the inbounds pass and dribbled up the court before hitting the shot over two defenders.
Tyler Ennis does not make mistakes when the game is on the line. In one-possession games in the final 5 minutes of regulation and overtime this season, Ennis is now 8-for-9 on field goals. He also has 6 assists and no turnovers in those situations.
Talib Zanna, who led Pitt (20-5, 8-4) with 16 points and 14 rebounds, hit two free throws to give Pitt a 56-55 lead before Ennis' winner.
It was Pitt's first loss at home to a top-five team in the 12-year history of the Petersen Events Center. The Panthers (20-5, 8-4) had been 9-0 against top-five teams and 13-1 against teams ranked in the top 10.
C.J. Fair led Syracuse with 14 points.
Pitt had a 54-48 lead with less than 2 minutes remaining, but Fair made a 3-pointer with 1:40 to go. He then hit a jumper to make it 54-53 with 51 seconds left. After Pitt missed on the other end, Ennis made two free throws with 10 seconds left to give the Orange the lead.
Pitt led 27-24 at halftime and built its lead to nine in the early stages of the second half when Lamar Patterson made a 3-pointer to make it 37-28 with 15 minutes remaining.
Syracuse stormed back with a 17-8 run and tied it on Trevor Cooney's 3-pointer with 6:53 to go, but Pitt regained control after Zanna converted a three-point play and freshman Jamel Artis sank two free throws for a 50-45 lead.
But it was all Syracuse after that. Pitt's only points in the final 1:59 came from Zanna's two free throws, and the Panthers were outscored 10-3 in the final 1:59.
Pitt had injury issues of its own. Senior forward and leading scorer Lamar Patterson had the thumb on his right hand wrapped for a second consecutive game. After going 1 for 9 in his previous outing against Virginia Tech, Patterson scored 13 points.
Pitt led by as many as seven in the first half. Patterson's 3-pointer with 4:30 to go before halftime capped a 10-3 run that gave the Panthers a 24-17 lead. It was the third 3-pointer of the half for the Panthers, who also had their way on the offensive glass against Syracuse.
The Panthers outrebounded Syracuse 18-11 in the first half and scored seven second-chance points from nine offensive rebounds.