The Cardinals were never in the contest with the Bulls, fumbling the opening kick-off that South Florida recovered for a quick 6-0 lead a mere eight seconds into the game.
It got worse from that point. South Florida dominated the action from start to finish and took a commanding 41-10 lead into halftime.
Louisville never mounted a challenge against the Bulls before or after the break. In total, the Cardinals committed seven turnovers - three Brian Brohm interceptions, one Hunter Cantwell interception and three lost fumbles.
The loss drops the Cardinals to 5-6 on the season and 2-4 in Big East conference standings. With one game remaining on Nov. 29 against Rutgers at home, Louisville, needing one more win to become bowl eligible, probably won't go bowling for the first time since 1997 when Ron Cooper coached his final team at U of L.
The 55 points Louisville's defense surrender were most points allowed by a U of L team since John L. Smith's first team lost to Southern Miss 56-21 in 1998.
Despite throwing three int's, Brohm became the Big East's all-time leading passer with 10,538 yards - 9,719 yards since Louisville joined the Big East in 2005.