Kolby Smith led the way for the Cardinals ground, rushing for 165 yards and two touchdowns, including a 31 yarder that sealed the win with less than 2:00 remaining in the game.
"The past two or three games I haven't run like I'm capable," Smith said. "Today, I hit the hole hard and got back to running like the old Kolby."
The Cardinals took control in the second half after starting out the game slowly on offense. Up just 7-6 at halftime, Louisville scored on its first possession of the second half to take a 14-6 advantage.
Freshman running back Anthony Allen scored his second touchdown early in the fourth quarter from one yard out to give Louisville a 21-6 lead. Syracuse closed the margin to 21-13 win just over 5 minutes left in the game, but Smith and the Cardinals marched 93 yards following Syracuse's touchdown, capped by Smith's 31-yard touchdown run, to put the game out of reach.
"We executed well in the second half," Louisville coach Bobby Petrino said. "If you take away the two turnovers we're right where we want to be offensively."
The Cardinals, who rushed for just 105 yards last week against Cincinnati, gained 223 yards on the ground against Syracuse. Brian Brohm completed 18-26 passes for 203 yards, but committed two turnovers.
Louisville sacked Orange quarterback Perry Patterson six times and held Syracuse to only 46 yards rushing. William Gay also intercepted Patterson, who threw for 303 yards, in the second half.
Louisville can now turn their attention to fourth-ranked West Virginia. The Cardinals host the Mountaineers next in a Nov. 2 showdown of unbeaten teams at Papa John's Cardinal Stadium. West Virginia, also 7-0, beat Connecticut Friday night, 37-11.