In Morgantown, W.Va., John Holifield ran for three touchdowns and 177 yards and John Talley threw three scoring passes as the Mountaineers spoiled Howard Schnellenberger's return to coaching.
West Virginia scored four second-quarter touchdowns to break a 7-7 tie.
West Virginia linebacker Fred Smalls recovered a fumble by John Adams at the Cardinals' 26, setting up Holifield's 18-yard touchdown run with 10:22 left in the first half to make it 14-7.
Talley then hit scoring passes of 45 yards to Grantis Bell and 35 yards to Calvin Phillips, and Holifield ran five yards for another touchdown with 41 seconds left to give the Mountaineers a 35-7 halftime lead.
Talley, who completed 13 of 17 passes for 166 yards, also hit a nine-yard scoring pass to tight end Gary Basil in the first quarter.
Holifield, a junior who gained only 311 yards last season, rushed for 148 yards on 14 carries in the first half. He carried five times in the second half, including a two-yard run for his third touchdown as the Mountaineers scored on their first possession of the third quarter to make it 42-7.
"Certainly today was no beginning toward building national prominence," said Schnellenberger, who coached Miami to the 1983 national championship. "Today was very disappointing to me, my staff and all those concerned with making Louisville a great football school. We really didn't give ourselves the opportunity to compete with West Virginia. We made errors on defense, in coverages and changes of strength."
His counterpart at West Virginia, Don Nehlen, offered some consolation: "We are not as good as some people may think and they are not as bad. I expected to win, but I never expected to score 52 points."