Houston (6-1) had six turnovers and Louisville turned that into 28 points en route to a 35-14 victory.
"We didn't execute at all," said Houston coach Billy Cook. "And we didn't execute on either side of the ball. We really didn't show up with the same team we've been playing with the last couple of weeks."
The defending Division 4-4A champions got things started on the first drive of the game and took a quick 7-0 lead over the Hilltoppers. Louisville (4-3) then spent the rest of the half taking advantage of Houston mistakes and turning those miscues into points.
The Wildcats converted a trio of Houston turnovers into 14 points in the first half and held a comfortable 21-0 lead at the break. One of those turnovers occurred in Louisville's end zone to turn away Houston's best drive of the opening half.
"There is no doubt turnovers is what killed us in the first half," said Cook. "We should've been in the game in the first half and we have to make those plays and execute. They were normal plays, too, that we've been making. That is what made it so difficult to understand."
After Louisville stretched its lead to 28-0 in the third quarter, the Hilltoppers did cut the lead to 28-14 thanks to Sharone Wright's 22-yard scoring toss to Gavin McQuary and Chris Thornton's 48-yard punt return for a touchdown.
But with under three minutes to go in the game, Houston committed its sixth and final turnover and Louisville put the game away with a 20-yard touchdown run by Cass Love on the ensuing play.
"Coming into the game we felt like we were pretty focused," Cook said. "But for whatever reason it didn't carry over to the field. Now we just have to make sure we are all on the same page and get ready for next week."
Wright rushed for 109 yards on 18 carries for Houston while Love led the Wildcats with 146 rushing yards and three touchdowns.