Following one season of college football with the Texas A&M Aggies, Murray played for the Oklahoma Sooners, where he won the Heisman Trophy as a junior.

He received consecutive Pro Bowl selections during his next two seasons, along with leading the Cardinals to the playoffs in 2021, their first appearance since 2015.

[15][16] As a true freshman in 2015, Murray competed with Kyle Allen before the season for the starting quarterback position.

[17] Allen won the job, with Murray appearing in games as a backup (primarily on plays involving the wildcat formation).

[26] With Mayfield heading to the NFL, Oklahoma considered Murray and Austin Kendall to start at quarterback in 2018.

[29] Murray helped lead Oklahoma to a Big 12 Championship win and an appearance in the College Football Playoff.

[41] Prior to his junior year with the football team, Murray said that he would report to spring training in 2019 to begin his professional baseball career.

[44] Some believed that Murray's pursuit of a football career at the expense of a potential one in baseball was a mistake because of his limited stature relative to a typical NFL quarterback.

[45][46] At the NFL Combine, Murray was not expected to match his listed height of 5 ft 10 in (1.78 m),[47] because colleges often exaggerate measurements to make players more formidable to opposing teams.

Murray's final measurements were 5 ft 10+1⁄8 in (1.78 m) and 207 lb (94 kg),[48] similar to that of then-Seattle Seahawks starting quarterback Russell Wilson.

Despite not taking part in individual drills at the combine, many saw Murray's draft stock improve because of his greater-than-expected measurements,[49][50][51] though some football scouts and pundits remain skeptical of the official listing.

[48] When leading Texas Tech's football program, Cardinals head coach Kliff Kingsbury said that he would hypothetically spend the draft's top selection on Murray.

[74] In Week 10, against the Tampa Bay Buccaneers, Murray threw for 324 passing yards, three touchdowns, and one interception in the 30–27 loss.

[77] Before the regular season finale against the Los Angeles Rams, Murray was listed as a game-time decision with a hamstring injury and ultimately played in the game despite being hurt.

[92] He helped the Cardinals mount a comeback win in the final seconds; down 26–30, the Cardinals drove down to the Buffalo 43-yard line with 11 seconds to go before Murray scrambled out of the pocket and connected with DeAndre Hopkins, who was surrounded by three Bills defenders, on a Hail Mary pass.

The resulting touchdown, dubbed the "Hail Murray", allowed Arizona to win 32–30 and take the division lead in the NFC West.

Murray participated as one of 4 players representing the NFC, and won the match, earning Madden NFL 21 Pro Bowl MVP.

[100] In Week 2 against the Minnesota Vikings, Murray finished with 400 passing yards, 31 rushing yards, two interceptions, and four total touchdowns as the Cardinals narrowly won 34–33 due to the Vikings missing a field goal with three seconds left in the fourth quarter.

[103] In Week 6 against the Cleveland Browns, Murray threw for 229 yards and four passing touchdowns as the Cardinals won 37–14, improving to a league-best record of 6–0.

[105] Prior to Week 8, Murray had led the Cardinals to the best record in the NFL at 7–0 before getting injured in the final minute of the Thursday Night Football loss against the Green Bay Packers.

[107] In Week 14 against the Los Angeles Rams on Monday Night Football, Murray threw for 383 yards and two interceptions as the Cardinals lost 30–23.

However, the Cardinals missed two field goals and an extra-point, narrowly losing 22–16 and dropping their third consecutive game, having previously lost to the Lions in Week 15.

[113] On January 17, 2022, Murray made his NFL postseason debut in the Wild Card Round, losing to the Rams 34–11.

Murray struggled throughout the game, throwing for just 137 yards, two interceptions, and zero touchdowns, as well as setting a career low in passer rating (40.9).

[122] In Week 7 against the New Orleans Saints on Thursday Night Football, Murray threw for 204 yards and a touchdown on 20-of-29 passing as the Cardinals won 42–34, snapping an eight-game losing streak at home.

[123] In Week 8 against the Vikings, Murray scored his 100th career touchdown, becoming the 12th fastest player to reach that milestone.

[124] In Week 14 against the New England Patriots on Monday Night Football, Murray suffered a non-contact knee injury in the first quarter.

[140] Despite the identical record from the previous season, Murray expressed that "It's a complete 180" compared to last season and attributed the team's positive cultural shift to the belief and accountability instilled by first-year coach Jonathan Gannon and general manager Monti Ossenfort, stating, "Just to have guys upstairs that believe in it – really speak to it and hold everybody accountable.

"[141] In Week 2 against the Rams, Murray completed 17-of-21 passes for 266 yards and three touchdowns, earning a perfect passer rating as the Cardinals won 41–10.

[152][153] His cousin, Devin Duvernay, is a University of Texas alumnus and is a wide receiver for the Jacksonville Jaguars.