Mack was born in Los Angeles, California. He attended San Marcos High School in Santa Barbara, where he was named the Channel League's Co-Most Valuable Player on defense and earned a first-team all-league selection. He was also selected to the All-CIF team. In the classroom, he compiled a 4.2 GPA and an 1180 SAT score.
Mack signed a five-year contract with the Browns on July 25. During the 2009 NFL Season, Mack started on the Browns offensive line every game. After a shaky start, the Browns line, anchored by Joe Thomas, paved the way to three consecutive 100+ yard games by Jerome Harrison and one game in which Harrison ran for 286 yards, which stands at third all-time in one game. At the end of the regular season, Mack was selected as center on the All-Rookie team. He started all 16 games, committed only 1 penalty and allowed just 1 sack.
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.