He was signed by the San Francisco 49ers as an undrafted free agent out of college, and has also played in the NFL for the Cleveland Browns.

[7] During his senior season, 2012, Mullens threw for 3,649 yards and 40 touchdowns, against only seven interceptions, en route to winning the 2012 Gatorade Player of the Year award for the state of Alabama.

[11] In his second collegiate game, a loss to Marshall, Mullens became the first true freshman starting quarterback in Southern Miss history to pass for more than 300 yards in a single game, a feat never accomplished during his freshman year by the school's most famous football alumnus, Brett Favre.

[12] On November 30, 2013, Mullens played a key role in helping Southern Miss end its losing streak at 23 games with a five-touchdown performance against the University of Alabama-Birmingham, which also happened to be the college that he originally committed to.

Mullens' efforts were instrumental in a reversal of fortunes of the Southern Miss football program, with the team posting a 9–5 record for the year just two seasons after snapping its abysmal 23-game losing streak.

[17] He started all 14 games as the Golden Eagles finished with more than 7,000 yards of offense for the first time in school history.

[19] In four seasons at Southern Miss (2013–2016), Mullens played in 44 games (41 starts) and completed 928 of 1,546 attempts for 11,994 yards and 87 touchdowns.

[23] He entered training camp as the fourth backup quarterback on the depth chart behind veterans Brian Hoyer and Matt Barkley, and rookie C. J.

[24] On September 2, 2017, Mullens was waived as part of the 49ers' final roster cuts, but he was signed to the practice squad the next day.

[25][26] On January 2, 2018, the 49ers signed Mullens to a reserve/futures contract after he spent his entire rookie season on the practice squad.

[28][29] On September 26, 2018, the 49ers promoted Mullens to their active roster after starting quarterback Jimmy Garoppolo tore his ACL and was placed on injured reserve for the rest of the season.

During Week 13 against the Seattle Seahawks, Mullens finished with a career-high 414 passing yards, two touchdowns, and an interception as the 49ers lost by a score of 43–16.

[38] In the regular-season finale against the Los Angeles Rams, he finished with 282 passing yards, three touchdowns, and three interceptions in the 48–32 loss.

[44] On September 20, 2020, in a game against the New York Jets, Mullens came in after halftime after Jimmy Garoppolo suffered a leg injury.

[52] On December 22, 2020, it was announced that Mullens would miss the rest of the season with an elbow injury he suffered in the 49ers 41–33 loss against the Dallas Cowboys.

[60] Mullens was elevated to the Browns' active roster on October 21, 2021, prior to their game that evening,[61] and reverted to the practice squad the following day.

During the game, Mullens threw a touchdown pass late in the fourth quarter, giving the Browns the lead.

Following the loss, the Vikings benched Mullens ahead of their Week 17 matchup against the Green Bay Packers in favor of Jaren Hall but re-entered at half-time when they scored just three points.