In the annual rivalry game against Oklahoma State, he had 136 rushing yards and two rushing touchdowns. On October 24, against Texas Tech, he had 154 rushing yards and two rushing touchdowns. In addition, he ran for 27 yards on five carries against Akron. In his first career game, Mixon had a 76-yard touchdown reception, the longest catch ever by a Sooner freshman running back. He earned playing time his redshirt freshman year, playing in all 12 games with three starts. He was suspended from the Oklahoma football team for the 2014 season after a misdemeanor assault charge in October 2014. Mixon attended and played college football for the University of Oklahoma from 2014–2016. He had 47 offers, and ultimately chose Oklahoma over Alabama, California, Wisconsin, and UCLA. In January 2014, he committed to the University of Oklahoma to play college football. Mixon was ranked as a five-star recruit and the top-ranked running back in the nation by the recruiting network. His team went 22-2 overall and 10-0 in league play that season. He had a 12.2 PPG average and a free throw percentage of 57% and made 79 field goals. Mixon played in 16 basketball games for the Falcons. In his final year, he rushed for 1,704 yards and 23 touchdowns on 226 carries. In his junior year, he rushed for 1,443 yards and 21 touchdowns on 201 carries.

He rushed for 1,134 yards and 13 touchdowns as a sophomore on 171 carries.

He was a three-year starter at running back for the Freedom High School Falcons football team. Mixon attended Freedom High School, where he played football and basketball for the Falcons.

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