Syracuse (24-2, 11-2 Big East), which held off Connecticut 72-67 on Wednesday night after squandering a 16-point lead in the second half, had won 11 straight since a loss to Pittsburgh.
It was the fifth straight win over the Orange for Louisville (16-9, 7-5), which was 0-4 against ranked teams entering the game. Its last win over a ranked team was a 10-point triumph over Syracuse last March.
Samuels scored his first points of the game on a pair of free throws with 7:46 left and followed with a hook off the glass to tie the game at 50. Mike Marra's 3 from the left corner gave the Cardinals a three-point edge and Samuels made a twisting layup through traffic to put Louisville up 55-52 with 5:14 left.
Six straight free throws by the Orange closed the gap to 62-58 with 64 seconds remaining, but Syracuse was unable to score again after Kris Joseph's slam dunk with 31.9 seconds left made it a two-point game.
Joseph was then called for an intentional foul on Smith, who sank both free throws.
Edgar Sosa and Marra each had 12 points to lead Louisville. Jared Swopshire had 10 points.
Wes Johnson had 14 points, Andy Rautins and Arinze Onuaku each had 12, and Joseph 10 for the Orange.
Rautins and Scoop Jardine missed 3-pointers in the final seconds and Rakeem Buckles' slam at the buzzer ended the big win for Louisville, which finds itself on the bubble for the NCAA tournament and was in desperate need of a signature win.
Sosa's 3-pointer from the left wing with 13:24 left broke the third tie of the second half and gave Louisville a 42-39 lead.
After three turnovers by the Orange and two more by the Cardinals as both teams repeatedly passed the ball around looking for an open man, Rautins hit consecutive 3s in transition in a 37-second span to put Syracuse back on top midway through the half.
Syracuse never got its high-powered transition game untracked against the Louisville defense, which limited the Orange to 41.4 percent shooting.
Syracuse entered the game leading the nation in field-goal percentage at 52.7 and ranked fourth in steals with 10.6 per game. The Orange only managed four steals against the Cardinals, who were patient and deliberate when the game was on the line.
In a 19-point loss on Thursday night at St. John's, the Cardinals fell behind 12-0 and didn't score in the game's first 6:46. Against the Orange, Louisville went scoreless over the first 3:47 before Swopshire scored in the lane.
Louisville continued its early game woes, making only one of its first nine shots, and fell behind 22-11 on Jardine's fastbreak layup with 8:14 left.
But Preston Knowles and Marra each hit 3s to key a 12-3 Louisville run in the final six minutes as the Cardinals stepped up their press and moved within 29-28 at halftime despite the awful start and no points from leading scorer Samuels.
Samuels picked up his second foul just 4:30 into the game and missed both shots he attempted in 11 minutes. He entered the game averaging nearly 16 points.