Mayfield was born on April 14, 1995 in Austin Texas, to James and Gina Mayfield, the second of two sons. James, a private equity consultant, encountered financial difficulties during his younger son’s senior year in high school. These struggles forced the Mayfields to sell their family home and move from rental home to rental home.

In his first start against SMU, Mayfield passed for 413 yards and four touchdowns. His 43 completions of 60 attempts broke a school record held by Billy Joe Tolliver, and fell only four completions short of the NCAA Division I FBS single-game record for completions by a freshman, held by Luke McCown. For his performance, Mayfield was named Big 12 Conference Offensive Player of the Week – the first freshman Texas Tech quarterback to be named so since former Red Raider head coach Kliff Kingsbury in 1999. The game featured the last four former Lake Travis quarterbacks combined on both teams: Garrett Gilbert, Michael Brewer, Collin Lagasse, and Mayfield.

Mayfield started for the first time in the Browns’ next game, making him the 30th starting quarterback for the Browns since their return to the NFL in 1999, in a 42–45 overtime loss to the Oakland Raiders. In Week 5, Mayfield threw for 342 passing yards and one touchdown as he earned his first victory as a Browns’ starter, in 12–9 overtime victory over the division rival Baltimore Ravens. In Week 10, Mayfield led the Browns to a 28–16 victory over the Atlanta Falcons. throwing for 216 yards, three touchdowns, and a passer rating of 151.2, with no turnovers. The following week, Mayfield led the Browns to their first road win since the 2015 season, against the Cincinnati Bengals. He completed 19 of 26 passes for 258 yards and four touchdowns. In Week 12, in a 13–29 loss to the Houston Texans, Mayfield passed for 397 yards, one touchdown, and three interceptions. Mayfield bounced back in the following game, a 26–20 victory over the Carolina Panthers, going 18 of 22 for 238 passing yards and one touchdown.

While Mayfield was considered by many to be the favorite for Offensive Rookie of the Year during the 2018 season, the award was given to Giants running back Saquon Barkley. On the annual Top 100 Players list for 2019, Mayfield’s peers named him the 50th best player in the league, one spot behind teammate Myles Garrett. He was named 2018 PFWA All-Rookie, the second Cleveland quarterback to receive this honor since Tim Couch in 1999.

In Week 6 against the Seattle Seahawks, Mayfield threw for 249 yards, one touchdown, and three interceptions. He also rushed four times for 35 yards and his first career rushing touchdown as the Browns lost 32–28. Mayfield recorded his first game of the season with two or more passing touchdowns in Week 10 against the Buffalo Bills, completing 26 of 38 passes for 238 yards and two touchdowns, including the game-winner to Rashard Higgins, as the Browns snapped a four-game losing streak with a 19–16 win. Four days later on Thursday Night Football against the Pittsburgh Steelers and former Big 12 Conference rival Mason Rudolph, Mayfield recorded his first career win against Pittsburgh, accounting for three total touchdowns (2 passing, 1 rushing) as Cleveland won 21–7. In Week 12 against the Miami Dolphins, Mayfield threw for 327 yards, three touchdowns, and one interception in the 41–24 win. In Week 17 against the Cincinnati Bengals, Mayfield became the first Cleveland Browns QB to start all 16 games in a season since Tim Couch in 2001. In the game, Mayfield threw for 279 yards, three touchdowns, and three interceptions as the Browns lost 33–23. Mayfield finished the 2019 season with 3,827 passing yards, 22 touchdowns, and 21 interceptions as the Browns finished with a 6–10 record.

After playing for Texas Tech, Mayfield transferred to the University of Oklahoma in January 2014, but had not contacted the Sooners coaching staff. Mayfield further elaborated in an interview with ESPN that he sought to transfer due to scholarship issues and a perception that he had earned the starting position and that further competition was not “really fair.” The alleged scholarship issues were denied by Texas Tech coach Kliff Kingsbury.

In February 2014, Oklahoma head coach Bob Stoops confirmed that Mayfield would be walking on for the Oklahoma Sooners. Mayfield was not eligible to play until the 2015 season, and he lost a season of eligibility due to Big 12 Conference transfer rules following an unsuccessful appeal of his transfer restrictions.

When Mayfield transferred from Texas Tech to Oklahoma after his freshman year, he filed an appeal to the NCAA to allow him to be eligible to play immediately at Oklahoma on the basis that he was a walk-on and not a scholarship player at Texas Tech; therefore, the transfer rules that apply to scholarship players should not be applicable to his situation. The NCAA denied his appeal as he did not meet the criteria. Big 12 Conference rules additionally stipulate that intra-conference transfers will lose one year of eligibility over and beyond the one-year sit-out imposed by the NCAA. Mayfield attempted to appeal his initial loss of eligibility to the Big 12 Conference faculty athletics representatives but was denied in September 2014.

Officials from Oklahoma asked Texas Tech officials to authorize Mayfield’s immediate eligibility, but Texas Tech officials objected and declined the request before granting a release in July 2014. Mayfield was thus forced to sit out the 2014 season, while also losing one year of eligibility as required by the rules.

On August 24, 2015, Mayfield was named the starting quarterback for the Sooners after winning an open quarterback competition against Trevor Knight. On September 6, 2015, Mayfield started against Akron. Mayfield totaled 388 passing yards with three passing touchdowns on 23 completions in the 41–3 win. In the second game of the 2015 season, Mayfield started at Tennessee at Neyland Stadium. The Sooners were ranked 19th at the time and the Volunteers were ranked 23rd. Mayfield started off very slow in the game, not even reaching midfield until the 13-minute mark of the fourth quarter. Oklahoma came back from a 17-point deficit to win the game by a score of 31–24 in double overtime. Mayfield threw for 187 yards and three touchdowns on 19 completions while throwing two interceptions early in the game. In the third game of the season, Mayfield started against Tulsa. He had a career day, throwing for 487 yards and four touchdowns, including 316 yards in the first half. Mayfield also ran for 85 yards and two touchdowns in the 52–38 win.

In December 2016, it was announced that Mayfield and his top receiving target, Dede Westbrook, would be finalists for the 2016 Heisman Trophy. It was also announced that they would play in the 2017 Sugar Bowl. Mayfield ended up finishing third in the Heisman voting.

On June 1, 2016, the Big 12 faculty athletic representatives voted against a rule proposal that would have allowed walk-on players to transfer within the conference and not lose a year of eligibility. The next day, the rule proposal was amended to allow walk-on players, without a written scholarship offer from the school they are transferring from, to transfer within the conference without losing a season of eligibility. The faculty athletic representatives approved the amended proposal with a vote of 7–3. The rule change made Mayfield eligible to play for Oklahoma through the 2017 season. Texas Tech voted in favor of the rule.

In the 2017 Sugar Bowl, Mayfield helped lead the Sooners to a 35–19 victory over Auburn. He finished the game with 19 completions on 28 attempts for 296 passing yards and two touchdowns, earning him the MVP award.

On September 9, 2017, after a win against the Ohio State Buckeyes in Columbus, Mayfield planted the Sooners’ flag in the middle of the painted “O” at Ohio Stadium, causing a major public backlash. Mayfield issued an apology shortly afterwards.

On November 4, 2017, Mayfield threw for a school-high 598 yards against in-state rival Oklahoma State. Mayfield finished 24-for-36 with five passing touchdowns and one rushing touchdown, and Oklahoma won the game by a score of 62–52. Mayfield completed his career 3–0 as the starting Oklahoma quarterback in the Bedlam Series.

In November 2017, Mayfield was under fire again after an interaction during the game against Kansas. Mayfield was seen grabbing his crotch and mouthing “Fuck you!” at the coach of the opposing team. He also told their fans to “Go cheer on basketball.” In response, Mayfield issued another public apology. Days after the 41–3 victory over Kansas, Sooners head coach Lincoln Riley announced that Mayfield would not start or be the captain during the upcoming game against West Virginia due to his actions against Kansas.

On December 2, 2017, with the return of the Big 12 Championship Game after a six-year hiatus, Mayfield led Oklahoma to its third straight Big 12 championship, with Oklahoma beating the TCU Horned Frogs 41–17. Mayfield won MVP honors while Oklahoma clinched a second playoff berth in three years. A month later, the Sooners lost to the Georgia Bulldogs 54–48 in the 2018 Rose Bowl, which served as the national semifinal game.

On December 9, 2017, Mayfield won the 2017 Heisman Trophy with a sweeping majority. He received 732 first-place votes and a total of 2,398 points. This amount translated to 86% of the possible points and the third highest percentage in Heisman history. In addition, Mayfield became the first and only walk-on player to ever win the Heisman Trophy.

The Cleveland Browns selected Mayfield with the first overall pick in the 2018 NFL Draft. Mayfield signed a four-year rookie contract with the Browns on July 24, 2018, with the deal worth $32.68 million in guaranteed salary.

On November 8, 2020, Mayfield was placed on the reserve/COVID-19 list after being in close contact with a person who tested positive for the virus but was reactivated three days later.