[2] Sanders was rated a four-star prospect and initially committed to play college football at Florida Atlantic before flipping to Jackson State after his father was named head coach.

[3][4] Sanders enrolled at Jackson State in January 2021, but was ineligible to play for the team in its spring 2021 season, which was abbreviated and delayed from its normally intended 2020 schedule due to COVID-19.

[6] He was named the Southwestern Athletic Conference (SWAC) Freshman of the Year and second team All-SWAC and won the Jerry Rice Award as the most outstanding freshman in the NCAA Division I Football Championship Subdivision, becoming the first player from a historically black college or university (HBCU) to win the award.

[9] He completed 70.6% of his pass attempts for 3,732 yards with 40 touchdowns and six interceptions as a sophomore and was named the SWAC Offensive Player of the Year.

[14] In his first game for the Buffaloes, Sanders completed 38 of 47 pass attempts for a school-record 510 yards and four touchdowns in the team's 45–42 win over 17th-ranked TCU.

He finished the season with 4,134 passing yards and 37 touchdowns, with him earning Big 12 Offensive Player of the Year honors and named the winner of the Johnny Unitas Golden Arm Award.