Senorise Perry ran for 100 yards and two touchdowns, and Terry Bridgewater completed 16 passes for 250 yards and a TD for the Cardinals (3-0).
Louisville limited Kentucky (1-2) to a field goal in the first three quarters. The Wildcats rallied in the fourth with a Joe Mansour field goal and a 3-yard TD catch by Alexander Montgomery.
Kentucky's Maxwell Smith and Jalen Whitlow combined to complete 17-of-37 passes for 214 yards and an interception. The Wildcats also lost two fumbles while Louisville turned the ball over once.