The Buckeyes (5-0, 2-0 Big Ten) were trailing 23-13 in the third quarter but rode Hyde's explosive performance to their nation-best 18th straight win.
He carried the ball 26 times while also catching four passes for 38 yards as quarterback Braxton Miller was largely held in check, finishing 15-of-26 for 203 passing yards.
Corey Brown led the Buckeyes' receiving corps with six grabs for 127 yards.
Northwestern (4-1, 0-1), meanwhile, fell short in its bid to begin a season 5-0 for the first time since 1904-05.
The Wildcats' Trevor Siemian completed 13-of-18 passes for 245 yards with two TDs and an interception and a lost fumble.
Ryan Lawrence racked up 149 on eight catches for Northwestern.