He was selected by the Cincinnati Bengals in the first round of the 2012 NFL draft and he has also played for the Cleveland Browns, New York Giants, and Baltimore Ravens.

Having numerous offers, Zeitler narrowed his decision down to Wisconsin and Michigan,[3] before eventually picking the Badgers.

[7] Zeitler expected to be a second-rounder, having scheduled a draft-party for Day 2 of the Draft, before being surprised by the Cincinnati Bengals' late first-round selection.

[10][11] Zeitler was the eighth UW offensive lineman taken in the first round of an NFL draft since 1976, after Dennis Lick, Ray Snell, Paul Gruber, Aaron Gibson, Chris McIntosh, Joe Thomas, and Gabe Carimi.

On March 9, 2017, Zeitler signed a five-year, $60 million contract with the Cleveland Browns, making him the highest paid guard in the NFL.

[15] On March 13, 2019, the Browns traded Zeitler and Jabrill Peppers to the New York Giants, along with their first and third-round (originally acquired from the New England Patriots) picks in the 2019 NFL draft, in exchange for Odell Beckham Jr. and Olivier Vernon.

[22] On January 30, 2024, Zeitler was named to the Pro Bowl for the first time in his career as an alternate, replacing Joe Thuney of the Kansas City Chiefs.