McCarron was born and raised in Mobile, Alabama. He attended Our Lady of Lourdes Catholic School from kindergarten to fourth grade before transferring to St. Paul's Episcopal School. At the age of 5, McCarron was severely injured in a jet-ski accident and almost died. He first played football at Trimmier Park and then Langan Park in Mobile. He played on the same park team as Mark Barron. During McCarron's junior season of high school, St. Paul's went 14-1 and went on to win the state championship against Briarwood Christian School off a missed PAT. While attending St. Paul's, McCarron was recruited by several football programs in the Southeastern Conference, including Alabama, Auburn, Mississippi, and Tennessee. He committed to the Crimson Tide on May 3, 2008, becoming the only quarterback signed by Alabama for their 2009 recruiting class.
In his first season at Alabama, McCarron accepted a redshirt and did not play during the season as the team went 14–0 to capture the 2009 National Championship. During his redshirt freshman year, he did see some playing time, appearing in nine games as the Tide finished 10–3. His first collegiate touchdown pass came during the season opener when he connected with wide receiver Julio Jones on a 29-yard pass. He passed for a total of 389 yards and three touchdowns during the season.
After a tight competition for the starting quarterback position during spring practices, McCarron was named as the co-starting quarterback alongside Phillip Sims for the team's 2011 season opener versus Kent State, and later became the de facto starter by starting in every game. In his first start in college, he passed for 226 yards and one touchdown with two interceptions as Alabama won 48–7. His first road start for Alabama came the following week, as the Tide traveled to State College, Pennsylvania. His performance of 163 yards with no turnovers helped Alabama defeat Penn State 27–11, which came to be the last loss for legendary head coach Joe Paterno. Another solid performance, alongside running back Trent Richardson, helped him get a victory in his first SEC start, a 38–14 win versus No. 14 Arkansas.
During the course of his sophomore season, McCarron led an 11–1 overall record during the regular season, including 7–1 record in conference. Alabama's only loss of the season came during a 6–9 overtime defeat at the hands of #1-ranked LSU. During the game, he completed 16-of-28 passes for 199 yards with one interception. By remaining unbeaten during the rest of the regular season, Alabama again met LSU at the Superdome for the national championship. His performance of 234 yards passing earned him Offensive Player of the Game in a 21–0 rout of the Tigers. During his first season as starting quarterback, he passed for a total of 2,634 yards with 16 touchdowns and five interceptions and a BCS National Championship.
McCarron at quarterback during a game versus Western Carolina
McCarron had a strong start in his second year as starting quarterback for Alabama as the Tide started off the season with a 9–0 record. In his first five games of the season, he passed for 999 yards and 12 touchdowns with zero interceptions. His good start to the season, including a comeback victory over LSU, had several media members put him as a dark horse candidate for the year's Heisman Trophy. His first interception, and Alabama's first loss, of the season came in the team's 10th game of the season. In their first year in the SEC, Texas A&M and eventual Heisman-winner Johnny Manziel came into Bryant–Denny Stadium and upset Alabama 29–24. His second interception of the game seemingly sealed Alabama's loss, as he threw an interception on a fourth & goal pass with under two minutes remaining. Both he and Alabama rebounded to remain unbeaten during the rest of the regular season, which led them to the 2012 SEC Championship Game versus Georgia. With the help of running back Eddie Lacy, Alabama battled with the Bulldogs to win 32–28 and earn a shot to play for the 2013 BCS National Championship against No. 1 Notre Dame.
On December 12, 2012, ahead of their game versus Notre Dame, McCarron announced that he would be coming back to Alabama for his senior season. On January 7, 2013, Alabama met Notre Dame for the 2013 BCS National Championship. The Fighting Irish were led by their defense and Heisman runner-up Manti Te'o to an unbeaten 12–0 regular season record. However, their defense was overmatched as Alabama rolled 42–14 to capture their third BCS National Championship in four years behind McCarron's 264 yards and four touchdown passes, which allowed him to become the first quarterback to win back-to-back BCS titles. During his junior season, he threw for a school-record 30 touchdown passes in a season, as well as 49 touchdown passes over his career. He was named winner of the 2012 CFPA Quarterback Trophy on January 22, 2013.
McCarron made the cover of Sports Illustrated's October 30, 2013, edition, which asked whether he was one of the best college players ever. At that time, McCarron (whose team was 10-0) was a long shot for the Heisman Trophy.
As a senior in 2013, McCarron was again a second-team All-Southeastern Conference (SEC) selection. During the season he passed John Parker Wilson to become Alabama's all time passing yard leader. He also broke Greg McElroy's record for passing yards in a season with 3.063.