Virginia (2-3) entered the game tied for 117th in the 120-member Football Bowl Series in total offense, averaging more than 272 yards per game. The Cavaliers easily eclipsed that by halftime, with Jameel Sewell's passing accounting for 248 yards of Virginia's 337-yard total. Virginia finished with more than 500 yards (536) for the first time since 2004.
Simpson finished with 83 yards on 15 carries and 66 yards on four receptions.
Sewell was 20 of 30 for 308 yards in three quarters before turning the reins over to backup Marc Verica.
The Virginia defense did its share, too, in the only game this season between Big Ten and Atlantic Coast Conference teams.
Simpson's first two TD runs came after big plays by cornerback Ras-I Dowling. On Indiana's first possession, Dowling stripped the ball from receiver Terrance Turner, and Rodney McLeod scooped up the fumble and returned it 32 yards to the Indiana 38. Simpson scored on a 5-yard run five plays later.
Dowling's first interception of the season set up another 5-yard scoring run for Simpson, who also had TD runs of 3 yards and 1 yard before being injured late in the third quarter. The crowd roared when Simpson gave a thumbs-up sign as he was carted off the field to the locker room.
Indiana (3-3) drove into Virginia territory on its first possession of the second half, thanks in part to a 27-yard pass from Ben Chappell to Mitchell Evans, but Nick Freeland missed a 40-yard field goal attempt. The Hoosiers finally broke through with a 12-yard touchdown run by Bryan Payton with 8:18 left in the game.
Virginia's do-everything Vic Hall had his best game as a receiver since moving from quarterback, where he started the season. Hall, a cornerback during his first three seasons, had six receptions for 85 yards, including a 21-yard touchdown pass from Sewell - the first TD reception of Hall's career.
Sewell also had a 1-yard TD run to cap a 77-yard drive that put Virginia up 44-0 late in the third quarter.
Robert Randolph added field goals of 37 and 31 yards for the Cavaliers.