Mannion was redshirted as a freshman in 2010. As a redshirt freshman in 2011, he started 10 out of 12 games. He finished the season completing 305 of 473 passes for 3,328 yards, 16 touchdowns, and 18 interceptions. During his sophomore season in 2012, Mannion completed 200 of 309 passes for 2,446 yards, 15 touchdowns, and 13 interceptions. Mannion remained the starter in 2013. On September 21, 2013, Mannion threw for five touchdown passes against the Utah Utes, tying a school record held by Derek Anderson. The next game, On September 28, Mannion threw for six touchdown passes against the Colorado Buffaloes, setting a new school record for most passing touchdowns in a game. Mannion finished the 2013 season leading the Beavers to a 7–6 record, including a victory in the Hawaii Bowl over the Boise State Broncos on Christmas Eve. In the final game, Mannion threw for 259 yards, giving him a Pac-12-record, 4,662 yards passing for the season. He finished the season with a school-record 37 passing touchdowns. Remaining the starter his senior season in 2014, Mannion became the Beavers all-time leader in career passing yards and passing touchdowns during the season, passing Derek Anderson's records. Later in the year, he became the Pac-12's all-time leader in passing yards, breaking Matt Barkley's record. He finished the season with 3,164 yards and 15 touchdowns. For his career, Mannion started 43 games, completing 1,187 of 1,838 passes for 13,600 yards, 83 touchdowns and 54 interceptions.
Collegiate statistics
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Professional career
Mannion was rated as the sixth best quarterback in the 2015 NFL Draft by NFLDraftScout.com.
Mannion was selected by the St. Louis Rams in the third round, 89th overall, of the 2015 NFL Draft. He started his career as the third-string quarterback behind Case Keenum and Nick Foles in his rookie year in 2015.
2015 season
Mannion played in his first NFL game of his career during a Week 12 matchup against the Cincinnati Bengals in which the Rams lost 31–7. He was put in the game late in the fourth quarter, in relief of Nick Foles. He completed 6 passes out of 7 attempts for 31 yards, posting an 85.1 passer rating.
2016 season
Mannion started 2016 as the second-string backup quarterback behind starter Case Keenum and ahead of the first overall pick of the 2016 NFL Draft, Jared Goff. In the season-opening 28–0 loss against the San Francisco 49ers, Goff took over as the second-string quarterback, demoting Mannion back as the third-string backup quarterback. Mannion was promoted to second-string for the final two weeks of the season. In Week 17, on New Year's Day, Mannion completed 3 of 6 passes for 19 yards and an interception after starter Jared Goff was subbed out of the game in a 44–6 blowout loss to the Arizona Cardinals.
2017 season
Mannion started the 2017 season as the backup to Goff after Keenum went to the Minnesota Vikings during free agency. In the season opener against the Indianapolis Colts, Mannion came into the game to finish up in relief of Goff after the Rams were up 46–9 and again in Week 15 when they were up 42–7 over the Seattle Seahawks. Due to head coachSean McVay resting most of his starters for the playoffs and having the playoff seed locked in, Mannion started the regular season finale against the San Francisco 49ers. Mannion was 20-of-34 for 169 yards with no touchdowns or interceptions in the 34–13 loss.
On April 7, 2019, Mannion signed with the Minnesota Vikings. Mannion made his debut with the Vikings in Week 17 against the Chicago Bears as a result of the Vikings resting their starters with a playoff berth already clinched. During the game, Mannion threw for 126 yards and two interceptions in the 21–19 loss. On March 19, 2020, Mannion re-signed with the Vikings.