As a senior, he played in 12 games and threw for 3,521 yards and 27 touchdowns, in his first year as the starter for the varsity high school football team.

On September 21, 2013, Mannion threw for five touchdown passes against the Utah Utes, tying a school record held by Derek Anderson.

[8] 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.

[21][22] He started his career as the third-string quarterback behind Case Keenum and Nick Foles in his rookie year in 2015.

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.

[23] 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 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.

[24] 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.

When Vikings starter Kirk Cousins tested positive for COVID-19, Mannion was named as the starting quarterback for the team's Week 17 game at the Green Bay Packers.

On February 3, 2024, Mannion retired from professional football and joined the coaching staff of the Packers as an offensive assistant working with quarterbacks and the passing game.

[45][46] On January 30, 2025, Mannion was promoted to quarterbacks coach after Tom Clements' decision to retire from the NFL.