Andre McGee added 12 points and Louisville (21-6, 11-3 Big East) limited the Orange (17-10, 7-7) to 29 percent shooting to keep pace with No. 12 Georgetown atop the Big East.
Louisville won its season-high sixth straight showing it can survive without senior center David Padgett, who played only 17 minutes with foul trouble.
Arinze Onuaku led Syracuse with 16 points and Paul Harris added 13, but the Orange found few openings in Louisville's tough 2-3 defense. Syracuse entered the game tied with Georgetown in field goal percentage, making 49 percent of its shots from the field. The Orange managed barely half that against Louisville.
The Cardinals appeared to break open a close game when Williams finished a spectacular dunk over Donte Greene that gave Louisville a 50-40 lead with 8:20 to go.
Syracuse managed to get within one possession, cutting it to 52-50 on a putback by Onuaku with 2:20 remaining. Williams, however, hit a jumper from the corner and Earl Clark swiped the ball on Syracuse's next possession.
The Cardinals missed a shot, but Williams ran it down, eventually leading to McGee's fourth 3-pointer that pushed the lead to 57-50 with 53 seconds to go as Louisville ended the game on a 9-0 run.