The big plays helped the Gators (7-5) finish a disappointing season with a winning record while new coach Jim McElwain was among the spectators. Brian Poole also scored on a 29-yard interception return and Florida's defense repeatedly turned East Carolina's high-powered offense away from the end zone.
Shane Carden was 34 of 66 for 427 yards for the Pirates (8-5) but Hargreaves' pick with 1:20 left ended his day.
Harris left late in the third quarter with an apparent lower left leg injury and was replaced by former starter Jeff Driskel.
Driskel ran for a first down on a third-down play on the final drive to allow Florida to run out the clock.
Florida delivered the win under interim head coach D.J. Durkin, who took over for the bowl game after Will Muschamp's firing.
Reserve running back Adam Lane was named the game's MVP after rushing 16 times for 109 yards and a touchdown. He had only eight carries coming into the game, all coming in two lopsided wins.
East Carolina came in averaging 37.2 points a game but managed only a field goal in the fourth quarter despite a number of flirtations with the end zone.
Justin Hardy finished with 11 catches for 160 yards and Cam Worthy gained 130 yards on eight catches.
Florida's Harris was 5-of-11 passing for 123 yards and two touchdowns, including an 86-yarder to another little-used player Ahmad Fulwood early in the third quarter. It was the Gators' longest play from scrimmage this season.
Fulwood had just 113 yards receiving in the regular season. Driskel had 48 passing yards in what could be his final Florida game. McElwain said before the game Driskel had asked for a release from his scholarship.
Florida's offense mostly sputtered without Harris, but the defense delivered.
Trying to expand the lead, Driskel led the Gators into East Carolina territory before Josh Hawkins forced a fumble by receiver Chris Thompson.
East Carolina drove to Florida's 27 before getting forced back by a penalty and Dante Fowler Jr.'s third sack of the game in his Gators finale. Fowler has already said he's skipping his senior season to turn pro.
The Gators took over with 4:21 left and went three and out. With two incompletions, Florida burned only 44 seconds off the clock before giving it back to Carden and the Pirates' high-powered offense at their own 42.
Carden completed three straight passes, including a nifty catch and run by Hardy for 24 yards.
Then East Carolina caught a momentary reprieve. Isaiah Jones fumbled at the end of a catch, the ball squirted away from a Florida player and Jimmy Williams dove on it at Florida's 5.
Hargreaves, the Gators' All-Southeastern Conference cornerback, picked off Carden's pass two plays later.