D'Ernest Johnson rushed for 111 yards and two touchdowns, receiver Marquez Valdes-Scantling took an end-around 75 yards for a touchdown and caught a 4-yard scoring pass from Flowers, and Auggie Sanchez returned an interception 43 yards for a TD.
The Bulls (5-0, 2-0 American) overcame some rare struggles on defense and remained perfect under first-year coach Charlie Strong by scoring on 10 of the 12 possessions with the starting offense.
Flowers, the American's offensive player of the year in 2016, ran 16 yards for a touchdown and hit Tyre McCants for a 14-yard score. Darius Tice also had a 1-yard TD run for South Florida.
Thomas Sirk had two touchdown passes and two scoring runs to keep the Pirates (1-4, 1-1) in it for a while. He hit Davon Grayson for a 31-yard TD and Stephen Baggett with a jump pass for a 2-yard TD on the final play of the first half.
Three of their first five opponents are in this week's Top 25 - No. 12 Virginia Tech, No. 23 West Virginia and these Bulls - and they've beaten ECU by a combined 181-68.