Muñoz was the third overall pick in the 1980 NFL Draft by the Cincinnati Bengals. His selection was viewed as a major risk by many pundits since knee problems limited the 6 ft. 6 in., 280-pound Muñoz to just a combined eight games in his junior and senior seasons, though he did return for USC's 17–16 Rose Bowl win over Ohio State University on New Year's Day 1980.
However, Muñoz became a starter in his rookie season and remained a fixture at left tackle for the Bengals for 13 seasons and is considered one of, if not the greatest, offensive linemen in NFL history. Despite his history of injuries, Muñoz missed just three games during his first 12 seasons. His rigorous workout routine included working out in the weight room he had installed in his home and running three to four miles every day. In addition to his talents as a blocker, Anthony Muñoz was also a capable receiver, notching seven receptions for 18 yards and scoring four touchdowns on tackle-eligible plays, including one in 1984 from rookie quarterback Boomer Esiason against the Cleveland Browns in Cleveland.
After missing much of the 1992 season battling knee and shoulder injuries, Muñoz attempted to play a 14th season with the Tampa Bay Buccaneers, but he was released before the season started and decided to retire shortly after.
Muñoz was the Offensive Lineman of the Year in 1981, 1987, and 1988, and was awarded the NFL Players Association Lineman of the Year honors in 1981, 1985, 1988, and 1989. The NFL Alumni Association voted Munoz the Offensive Lineman of the Year four times (1987, 1989–1991).
In 1998, Anthony Muñoz was enshrined in the Pro Football Hall of Fame. He was the first Cincinnati Bengals player to be enshrined. Shortly after receiving the honor, Muñoz's hometown of Ontario, California renamed its Colony Park "Anthony Muñoz Hall of Fame Park". The renaming ceremony was held on June 26, 1998, and was attended by Muñoz, his family, city officials, and Ontario residents. The park, incidentally, is the place where Muñoz met his wife DeDe after a pickup softball game during his youth.
In 2002, the Anthony Muñoz Foundation was created to consolidate Muñoz's charitable activities and encourages area individuals and businesses to "...impact area youth mentally, physically and spiritually".