Following one season of college football with the Oklahoma Sooners, he played for the USC Trojans and won the Heisman Trophy in 2022 after setting single-season school records in passing yards and touchdowns.

[4] The highest-rated quarterback prospect of his class, Williams committed to play college football at the University of Oklahoma.

[14] On January 3, 2022, Williams entered the transfer portal, and on February 1, he announced that he had transferred to the University of Southern California to play for the Trojans, reuniting him with head coach Lincoln Riley, who had been the head coach for the Sooners before being hired away by the Trojans the previous November.

[23][24] He declared for the 2024 NFL draft following the season, finishing his college career throwing for nearly 10,000 yards with 120 total touchdowns.

[29] His improvisational abilities in college was touted by analysts as one of his biggest strengths, such as ESPN's draft analyst Mel Kiper Jr. describing him as a "fabulous playmaker", though skepticism was levied at his smaller size and tendency to play "hero ball" to find a better play rather than a safer option.

[30][31] NFL.com draft writer Lance Zierlein and Bleacher Report's Derrik Klassen compared Williams' profile to Kyler Murray,[27][32] while Fox Sports' Bucky Brooks and CBSSports.com drew parallels to Russell Wilson and Steve McNair.

[49] On Thanksgiving against the Detroit Lions, Williams threw three touchdowns and set a rookie record for consecutive passes without an interception, but poor late-game clock management cost the Bears a chance at a comeback as they lost their sixth straight game, resulting in the firing of head coach Matt Eberflus the following day.

[50][51] Williams led a game-winning drive in the season finale to snap the Bears' ten-game losing streak and their 11-game skid to the Green Bay Packers, marking their first win against them since 2018; the victory also prevented Williams from tying Troy Aikman's record for the most consecutive games lost by a first-overall rookie quarterback.

[54] He was also the first Bears quarterback to start every game in a season since Jay Cutler in 2009 despite being sacked a franchise-high 68 times, the third most in NFL history.