Keyes played college football at Purdue University, where he was an All-American in 1967 and 1968, and finished second on the 1968 Heisman Trophy voting. He was inducted into the College Football Hall of Fame in 1990. In his very first collegiate game, played on national television against eventual national champion Notre Dame, Keyes made his presence known by returning a fumble 94 yards for a touchdown. He played in the January 1967 Rose Bowl game, which Purdue won 14-13 over USC.