Due to suffering a shoulder injury in his senior season, Barkley was not selected until the fourth round of the 2013 NFL draft by the Philadelphia Eagles.

[1] As a freshman, Barkley threw for 1,685 yards and 10 touchdowns, but suffered a season-ending injury (broken collarbone) during the playoffs in a quarterfinal victory over Colton High School.

[2] The injury was caused by future University of Southern California (USC) teammate, running back Allen Bradford, who played linebacker in high school.

[3] Barkley's high school coach, Bruce Rollinson, permitted him to call his own plays, something he had never allowed a player to do during two decades at Mater Dei.

On January 23, 2008, Barkley verbally committed to USC, ending speculation that he might join UCLA, which had just hired coaches Rick Neuheisel and Norm Chow.

[14] Barkley's 2008 senior season started slow, throwing nearly as many interceptions as touchdown passes and the Monarchs barely keeping above .500; however, his performance turned around and Mater Dei rallied to 7–3 and entered the playoffs.

[16] Barkley finished his Mater Dei High School career as the all-time passing yardage leader in Orange County, surpassing the record that was set by Todd Marinovich in 1987.

[18][19] Soon afterward, he was moved back to the number one high school prospect in America by ESPN, having dropped to tenth during his senior season.

[7] Sources: After graduating from high school a semester early, Barkley enrolled in the University of Southern California in January 2009 so he could participate in spring practice with the USC Trojans football team.

Barkley adapted to the Trojans offense and gave strong performances during spring practices: trying for and making big plays but also throwing several key interceptions.

Impressing his coaches, Barkley climbed to the number two spot at the end of Spring behind Corp.[21][22] Afterward, ESPN NFL draft analyst Mel Kiper Jr. stated he believed that in "three years Matt Barkley—who will be a true freshman this year—will be the No.

"[23] On August 27, during fall practices, Carroll named Barkley the starter for the 2009 season opener against San Jose State.

Before a sold-out, raucous crowd at Ohio Stadium, Barkley led a game-winning, 86-yard drive late in the fourth quarter, earning significant praise from the sports media.

With Aaron Corp at the helm, the Trojans struggled in a major upset loss, falling to the unranked Huskies 16–13 while putting up the lowest number of passing yards for a USC team since Carroll took over the program in 2001.

[47] He had previously tied the single-game touchdown record thrice, sharing it with Rodney Peete, Carson Palmer, Matt Leinart, and Mark Sanchez.

[52] On December 22, 2011, at a press conference convened at Heritage Hall, Barkley announced that he would return for his senior year with the USC Trojans rather than entering the 2012 NFL draft.

[53] Barkley announced his return to USC in his own unique way by giving Coach Kiffin a homemade ornament for Christmas with a picture of them at the Colorado game, but on the back revealing the text "One more year."

Barkley has described his decision to stay at University of Southern California in his senior as "unfinished business", as he wanted to be part of a team that would be aiming for the BCS championship after a two-year postseason ban.

[58] Barkley was knocked out of that game by UCLA's Anthony Barr with a shoulder separating hit, prematurely ending his regular season.

On December 27, 2012, head coach Lane Kiffin announced Barkley would not play in the Sun Bowl due to the shoulder injury, effectively ending his college football career.

On October 20, 2013, Barkley saw his first NFL action against the Dallas Cowboys as he came in to relieve Foles, who left early in the fourth quarter due to a head injury.

[74] After Jay Cutler suffered a shoulder injury against the Giants, Barkley started the following week's game against the Tennessee Titans.

[75] Barkley completed 28 of 54 passes for 316 yards with three touchdowns, two interceptions, and a 72.8 passer rating, nearly rallying the Bears from a 20-point deficit in the fourth quarter before losing 27–21.

[78] On December 18, Barkley completed 30 passes for 362 yards, two touchdowns and three interceptions as the Bears nearly upset the Green Bay Packers, ultimately losing 30–27 on a last-second field goal.

[85][86] On November 13, 2017, Barkley re-signed with the Cardinals due to Drew Stanton possibly missing playing time as a result of a knee sprain.

[94] Barkley, making his first NFL start in two years, threw for 232 yards and two touchdowns in the 41–10 road victory, snapping the team's four-game losing streak.

[96] In Week 4 of the 2019 season, Barkley came into the game against the New England Patriots to relieve Josh Allen, who had experienced an in-game head injury.

[109] On August 26, 2022, in the Bills' last preseason game against the Carolina Panthers, Barkley served as the team's punter in addition to seeing substantial playing time at quarterback.

[13][17] For Christmas 2010, he spent his winter break in Nigeria "visiting orphans, widows, villagers and prisoners, doing construction work, distributing supplies and gifts and sharing daily fellowship".

[121] In 2012, Barkley led a group of 16 USC football teammates to Haiti, where they built houses and delivered more than 2,000 pounds of supplies for orphanages and schools.