Houston entered the contest as the nation's leader with a 1.76 ERA, but it was Louisville's pitchers that dominated the weekend.
All three weekend starters - Kyle Funkhouser, Jared Ruxer and Anthony Kidston - all picked up wins. Kyle McGrath threw 3.2 innings of shutout middle relief, while All-American reliever Nick Burdi gave up no runs in 2.1 innings of work to collect two saves.
The Cardinals won the Friday opener 4-2, followed by a 3-2 win on Saturday night. The bats opened up on Sunday as U of L claimed a 10-3 victory to improve to 27-8 overall and 7-2 in AAC play.
"It's not something we really thing about," McDonnell said of the sweep following Sunday's victory. "We just came in trying to play good baseball, especially Friday, game one, hostile environment and we were able to win a close game. Then Saturday we came in and won a close game again."
U of L became the first team to claim a series win against Houston and the Cardinals have now won five straight series against nationally-ranked opponents.
Louisville returns home to host nationally-ranked Kentucky at Jim Patterson Stadium on Tuesday evening.