The win was the 100th of head coach Jim Tressel's career at Ohio State (6-0, 2-0 Big Ten).
Pryor had a career-high day with 334 yards on 24-of-30 passing in just over three quarters of play. Daniel Herron ran for a pair of touchdowns for the Buckeyes, who have won 12 straight games dating back to last season.
Ben Chappell was 16-of-26 passes for 106 yards with two interceptions for the Hoosiers (3-2, 0-2). Chappell had set a school-record with 480 passing yards last week against Michigan.
Ohio State jumped off to a 31-0 halftime lead and ran up 477 yards in the game to Indiana's 210.