Witherspoon was the only true freshman to start on defense for the Illinois Fighting Illini in 2019.[1] He wound up playing in every game, making 33 tackles. As a sophomore in 2020, he recorded 33 tackles and two interceptions.[4][5]
He played and started 10 games his junior year in 2021, finishing with 52 tackles and one sack.[6] Witherspoon returned to Illinois his senior year in 2022, beginning the year as the Big Ten Conference leader in passes defended.[7]
A supremely confident player, Witherspoon was regarded as the leading trash-talker on the Fighting Illini team during his tenure. When asked about the biggest talkers on the squad, offensive teammate Isaiah Williams joked that "Spoon is number one. Spoon is at one and then we go to like five."[8]
"I gotta talk, it's just me. I can't live without doing it," Witherspoon acknowledged.[8]
During his senior year Witherspoon was named one of twelve finalists for the Jim Thorpe Award, presented to the nation's top defensive back.[7] He was selected as the 2022 Tatum–Woodson Defensive Back of the Year, an award given to the top defensive back in the Big Ten Conference, and was named a consensus All-American at the season's conclusion.[9]
In Week 4 of the 2023 season, Witherspoon recorded his first career interception on a pass from quarterback Daniel Jones in a 24-3 win against the New York Giants. He returned the interception 97 yards for a pick-six,[13] the second-longest pick-six in team history, the longest being a 98 yard pick six by Bobby Wagner against the San Francisco 49ers in Week 13 of the 2018 season.[14] That same game, Witherspoon became the third rookie in NFL history to record 2.0+ sacks and a pick-six in a single game, along with Todd Shell and Andy Katzenmoyer, and the first player, rookie or not, to record both 2.0+ sacks and a 95+ yard pick six in a game since sacks became an official stat in 1982.[15] For this performance, Witherspoon won National Football Conference Defensive Player of the Week.[16] As a rookie, he appeared in 14 games and started 13. He finished with three sacks, 79 total tackles (56 solo), one interception, 16 passes defended, and one forced fumble.[17] He was named to the PFWA NFL All-Rookie Team.[18] He earned Pro Bowl honors.[19]