Mack played for the California Golden Bears football team while attending the University of California, Berkeley. He made 39 consecutive starts for the Golden Bears registering 256 key blocks/knockdowns, 32 touchdown-resulting blocks and 29 down field blocks. Mack compiled a 3.61 undergraduate GPA at the University of California, Berkeley as a legal studies major. He graduated in 2008 and played the 2008 season as a graduate student in education. He won the Draddy Trophy, also dubbed the “academic Heisman”, for his academic success in 2008, becoming the first Cal player and the second consecutive center to earn the trophy, following Dallas Griffin of Texas. He also won the Morris Trophy in 2007 and 2008, making him the third offensive lineman and the first since Washington’s Lincoln Kennedy in 1991 and 1992 to win the award twice. Mack also represented Cal at the 2009 Senior Bowl.

Projected as a first-to-second rounder by Sports Illustrated, Mack was the highest ranked center available in the 2009 NFL Draft. He was drafted by the Cleveland Browns with the 21st overall selection. He was the first Golden Bears offensive lineman selected in the first round since Tarik Glenn in 1997.

During the 2010 NFL season, Mack again started every game for the Browns. He was named to the 2011 Pro Bowl roster as a second alternate to replace Nick Mangold. During week 5 of the 2011 NFL season, Mack played through appendicitis during a loss to the Tennessee Titans. Mack had an appendectomy during Cleveland’s bye week and came back and started against the Oakland Raiders the week after the bye week.

On December 27, 2013, Alex Mack was voted to his first Pro Bowl Selection, after having been added in 2011 to replace an injured player.

On April 9, 2014, it was announced that the Jacksonville Jaguars had offered Mack a five-year contract, worth reportedly $42 million. The Browns had a maximum of five days to match Jacksonville’s offer, which they did on April 11. Mack had been previously assigned the transition tag, nullifying his free agency unless a team signed Mack to an offer sheet. During Week 6 against the Pittsburgh Steelers on October 12, 2014, Mack was carted off the field due to a leg injury. X-rays tested positive that his leg had a broken fibula, forcing Mack out for the rest of the 2014 campaign. Prior to Mack’s injury, he had never missed a single snap in his professional career. On March 2, 2016, Mack voided his contract with the Cleveland Browns thus making him a free agent.

On March 9, 2016, Mack signed a five-year, $45 million contract with the Atlanta Falcons, including $28.5 million in guaranteed money.

In the 2016 season, Mack and the Falcons reached Super Bowl LI , where they faced the New England Patriots. Mack was the starting center in the game for the Falcons. In the Super Bowl, the Falcons fell in a 34–28 overtime defeat.

On December 19, 2017, Mack was named to his fifth Pro Bowl.

On December 18, 2018, Mack was named to his sixth Pro Bowl.