Hancock connected on a 3-point shot with 53 seconds to play to break a 48-48 tie and the Cardinals (24-5, 12-4 Big East) relied on free throws to hold the Orange (22-7, 10-6) off the rest of the way.
Louisville has won five in a row and gained a measure of payback for their January loss to Syracuse, which knocked the Cardinals out of the No.1 ranking. Syracuse lost its third consecutive game.
C.J. Fair led Syracuse with 19 points. James Southerland came off the bench to score 13.
Neither team shot well from the field. Syracuse shot 35.7 percent while Louisville shot 36 percent from the field and a modest 58.3 percent from the free throw line.