The Cleveland Browns selected him first overall in the 2018 NFL draft.
As a rookie, Mayfield threw 27 touchdown passes, setting an NFL rookie record that stood until Justin Herbert broke it in 2020. In his NFL debut, he led the Browns to a comeback victory that ended the franchise's 19-game winless streak. In 2020, he helped Cleveland make its first playoff appearance since 2002 and win its first playoff game since 1994. After Cleveland acquired Deshaun Watson, Mayfield was traded to the Carolina Panthers in 2022 and later played for the Los Angeles Rams.
Mayfield signed with Tampa Bay in 2023. In his first two seasons with the Buccaneers, he helped the team win consecutive NFC South titles and a playoff game, and he was selected to the Pro Bowl in both seasons. His career postseason passer rating of 105.9 is the highest in NFL history among quarterbacks with at least 150 attempts.