The junior quarterback was responsible for four touchdowns -- three passing, one rushing.
The 2016 Heisman Award-winner became the first player in FBS history to throw for 3,000 yards and rush for 1,000 in consecutive seasons. Jackson also surpassed former Clemson quarterback Deshaun Watson on the ACC's list for career total yards.
The win makes Louisville (6-4, 3-4 ACC) bowl eligible for the eighth consecutive year. Virginia falls to 6-4, 3-3.
Jackson completed 15 of 26 passes without an interception. He carried 15 times and ripped off a 68-yard scoring run in the first quarter.
Virginia quarterback Kurt Benkert finished with 214 passing yards and a touchdown, but he was sacked four times.
Jaylen Smith snared touchdown receptions of 21 and 24 yards in the third quarter, the latter a one-handed, highlight-reel-worthy grab to put the Cardinals up 31-14. It was the junior's first trip to the end zone since Week 3 against Clemson.
Virginia caught a break late in the third quarter after a Reggie Bonnafon muffed punt, recovered by Joe Spaziani, set up the Cavaliers on the Louisville 33-yard line. The momentum was short-lived, however, when junior safety Dee Smith intercepted Benkert to quickly quash the possession.
Freshman Dae Williams found the end zone shortly thereafter on a 3-yard run for a 38-14 lead.
Jordan Ellis added a late 3-yard rushing touchdown for the Cavaliers.
Chris Sharp got the scoring going with 10:20 left in the first quarter on a 7-yard touchdown run to put Virginia up early. The offense struggled during the first half, but put together a late drive that culminated when Benkert hit sophomore tight end Evan Butts for a 25-yard touchdown with 48 seconds remaining in the second quarter to cut Louisville's lead to 17-14.