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On March 5, 2020, Mullens was assigned a one-year, $750,000 exclusive-rights free agent tender by the 49ers. He signed the contract on May 1, 2020.

During the 2019 season, Mullens primarily served as the backup to Jimmy Garoppolo. He only appeared in one game in the 2019 season.

Mullens has an older brother, Frank, and an older sister, Heather. On August 30, 2019, Mullens and his wife, Haleigh, had their first child, Luke.

On September 1, 2018, Mullens was waived by the 49ers and was signed to the practice squad the next day. 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. The terms of his new contract were for two years and $1.05 million.

On November 1, 2018, Mullens was named the starter for the 49ers' Week 9 game against the Oakland Raiders on Thursday Night Football after Beathard suffered a wrist injury in the previous game against the Arizona Cardinals. Mullens finished his NFL debut and first career start completing 16 of 22 pass attempts for 262 yards and three touchdowns as the 49ers won by a score of 34–3. His passer rating of 151.9 was the highest since 1970 for a quarterback with at least 20 passing attempts in a debut. Mullens was also the first player in 49ers history to throw three touchdowns in his first game for the team. He completed a 24-yard touchdown pass to wide receiver Pierre Garçon in the first quarter to mark his first NFL touchdown. The following week against the New York Giants, Mullens threw for 250 yards, one touchdown, and was intercepted twice by linebacker BJ Goodson as the 49ers lost by a score of 27-23 on Monday Night Football. Mullens made his first road start during Week 12. Facing the Tampa Bay Buccaneers, he threw for 221 yards, one touchdown, and two interceptions as the 49ers lost by a score of 27-9. 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. In Week 14 against the Denver Broncos, he passed for 332 yards, two touchdowns, and an interception as the 49ers won by a score of 20-14. In Week 15, Mullens threw for 275 yards and a touchdown to help the 49ers defeat the Seattle Seahawks in overtime by a score of 26–23, marking the first time the 49ers beat the Seahawks since 2013. 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.

Mullens finished the 2018 season with 2,277 passing yards, 13 touchdowns, and 10 interceptions.

On May 4, 2017, Mullens signed with the San Francisco 49ers as an undrafted free agent. He entered training camp as the fourth backup quarterback on the depth chart behind veterans Brian Hoyer and Matt Barkley, and rookie C. J. Beathard.

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. On January 2, 2018, the 49ers signed Mullens to a reserve/futures contract after spending his entire rookie season on the practice squad.

On October 1, 2016, against the Rice Owls, he threw for a collegiate career-high 591 yards, four touchdowns, and one interception in the 44–28 victory.

In the 2015 regular season, Mullens completed 331 of 521 passes (63.5%) for 4,476 yards and 38 touchdowns — school records for passing yardage and touchdown passes. He ranked sixth among NCAA Division I FBS quarterbacks in passing yardage. 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 24-game losing streak.

After starting the 2013 season with a 0–6 record, mired in an 18-game losing streak, Southern Miss head coach Todd Monken inserted true freshman Mullens as a starter for game seven, a home game against the North Texas Mean Green. The young team was overmatched by North Texas, however, suffering a 55–14 loss in which Mullens went 12-for-31 passing for 210 yards and one touchdown, while suffering three interceptions and a lost fumble.

On November 30, 2013, Mullens played a key role in helping Southern Miss end its losing streak at 24 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 passed for 1,776 yards as a freshman in 2013 and 2,470 yards as sophomore in 2014.

In four seasons at Southern Mississippi (2013–2016), played in 44 games (41 starts) and completed 928 of 1,546 attempts for 11,994 yards and 87 touchdowns. In 2016, made 11 starts and completed 243 of 384 attempts, for 3,272 yards and 24 touchdowns, averaging 297.5 passing yards per game. He started all 14 games as a junior in 2015 as the Golden Eagles finished with more than 7,000 yards of offense for the first time in school history. In 2014, he started 10 games and completed 218 of 365 attempts for 2,470 passing yards and 12 touchdowns.

Mullens played football for Spain Park, emerging as the team's starting quarterback. 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. He had totaled 8,605 career passing yards, finishing his high school career with the 7th most passing yards in AHSAA history, to go along with 40 passing touchdowns.

Nicholas Clayton Mullens (born March 21, 1995) is an American football quarterback for the San Francisco 49ers of the National Football League (NFL). He played college football for the Southern Miss Golden Eagles football team, where in 2015 he set single-season school records for passing yardage (4,476) and number of touchdown passes (38) breaking Brett Favre's past record in Southern Miss.

Mullens was born to Suzanne and Mark Mullens on March 21, 1995 in Little Rock, Arkansas and grew up in Hoover, Alabama, a suburb of Birmingham. He is the grandson of Ernie Tabor, who was a pitcher for the Philadelphia Phillies in the 1950s. His uncle, Scott Tabor, pitched for the Arkansas Razorbacks baseball team and holds the record for most career wins. He graduated from Spain Park High School in Hoover.