The second-ranked Buckeyes trailed by one at halftime, but surged past Indiana in the second half for a 49-21 season-opening win in Bloomington.
J.T. Barrett threw for 304 yards and three touchdowns and added 61 yards and a score on the ground.
True freshman running back J.K. Dobbins finished with 181 yards on 29 carries to lead Ohio State. Parris Campbell caught six passes for 136 yards and a score.
The Buckeyes will host eighth-ranked Oklahoma next Saturday.