Reed, last season's FBS passing yards leader at 4,746, was 29-of-50 passing for 336 yards without an interception. His 16-yard rushing TD tied the game with the score 17-17 at halftime.
USF had a first down at the WKU 4 but Byrum Brown was intercepted in the end zone by Aaron Key who returned it to the Hilltoppers' 29 early in the fourth quarter.
Lucas Carneiro extended WKU's lead with a 42-yard field goal before JaQues Evans stripped-sacked Brown and returned the fumble 27 yards for a touchdown with just under three minutes remaining and seal the outcome.
Brown rushed for 160 yards on 25 carries with two TDs. He was 15 of 34 for 166 yards passing with one TD but two interceptions. The Bulls outgained the Hilltoppers 540-465.
Alex Golesh lost in his head-coaching debut.
AP college football: https://apnews.com/hub/college-football and https://apnews.com/hub/ap-top-25-college-football-poll