Ryan Nassib threw for 246 yards, Jerome Smith ran for 144 yards and Syracuse handed No. 11 Louisville its first loss of the season in a 45-26 victory.
Playing in the last home game of his SU career, Nassib directed an offense that gained 524 total yards. Nassib went 15 of 23 and passed Marvin Graves as the school's career leader in passing yards.
The Orange scored on five straight possession to break a 10-10 tie.
Syracuse (5-5, 3-3) blew the game open with three touchdowns in the second quarter and Louisville (9-1, 4-1) allowed more points than it had in any game this season.
Teddy Bridgewater completed 36-of-49 passes for 426 and three touchdowns for Louisville.
The Cardinals ran for just 48 yards in the game. Senorise Perry was lost to a knee injury early in the game and didn't return.
U of L now has an open week before playing host to Connecticut on Nov. 24 and then ending the season at Rutgers on Nov. 29.