In the playoffs against Fenwick High School, he guided his team to a 32–31 win, after coming back from a 6–31 second-quarter deficit, by tallying 413 passing yards and 5 touchdowns.

[2][3] As a redshirt freshman in 2015, he took over the starting quarterback job that was left open after Trevor Siemian graduated.

He tore his right ACL in the 2017 Music City Bowl against the University of Kentucky, while making a reception on a trick play.

[9] As a senior in 2018, he was limited by his previous right knee injury, coming back with less than 8 months of recovery.

21 ranked University of Iowa, earning Northwestern the 2018 Big Ten Conference West title.

His 53 consecutive starts at quarterback is the most ever in the Big Ten and tied for the most with Colt McCoy in all of the Power Five conferences,[citation needed] and over those 4 years Clayton set several Northwestern career records including wins (35), passing yards (10,731), completions (991) and passing touchdowns (61).

He is the only quarterback in Big Ten history to pass for 10,000 yards and rush for 20 touchdowns in his career.

[20] The signing reunited him with offensive coordinator Jason Garrett, who was his head coach with the Cowboys.

[27] He was named the team's starting quarterback, even though he showed inconsistent play in the first two contests, while throwing 4 interceptions.