Gregg was a key player on the Packers dynasty of head coach Vince Lombardi that won five NFL championships and the first two Super Bowls in the 1960s. He played mostly at right tackle, but also filled in at guard. Gregg earned an "iron-man" tag by playing in a then-league record 188 consecutive games in sixteen seasons, from 1956 until 1971. He also won All-NFL acclaim eight straight years from 1960 through 1967 and was selected to play in nine Pro Bowls.
Gregg closed his career with the Dallas Cowboys, as did his Packer teammate, cornerback Herb Adderley. They both helped the Cowboys win Super Bowl VI in January 1972, making them the only players (along with former teammate Fuzzy Thurston, who was on the Baltimore Colts world championship team in 1958) in professional football history to play on six teams that won World Championships. Gregg wore jersey number 75 for fifteen seasons in Green Bay, but that number belonged to Jethro Pugh in Dallas, so Gregg wore number 79 for his final season in 1971.
Vince Lombardi claimed "Forrest Gregg is the finest player I ever coached!" in his book Run to Daylight.  In 1999, he was ranked number 28 on The Sporting News' list of the 100 Greatest Football Players, ranking him second behind Ray Nitschke among players coached by Lombardi, second behind Anthony Munoz (whom he coached) among offensive tackles, and third behind Munoz and John Hannah among all offensive linemen.
After serving as an assistant with the San Diego Chargers in 1973, he took a similar position the following year with the Browns. After head coach Nick Skorich was dismissed at the conclusion of the 1974 season, Gregg was promoted to head coach in 1975, a position he held through 1977.
When his longtime former teammate Bart Starr was fired after nine years as head coach of the Packers in December 1983, Gregg was allowed out of his contract with the Bengals to take over in Green Bay. He finished his NFL coaching career with the Packers, leading them for four seasons, 1984 through 1987. Gregg's overall record as an NFL coach was 75 wins, 85 losses, and one tie. He also won two and lost two playoff games.
Gregg voluntarily left the Packers in January 1988 and took a salary reduction to take over at SMU, his alma mater. He was brought in to revive the Mustang football program after it received the "death penalty" from the NCAA for massive violations of NCAA rules. Although the NCAA had only canceled the 1987 season, school officials later opted to cancel the 1988 season due to fears that it would be impossible to field a competitive team; nearly every letterman from the 1986 squad had transferred elsewhere. Although Gregg knew that any new coach would be essentially rebuilding the program from scratch, when acting president William Stalcup asked him to return, he felt that he could only accept.
As it turned out, when Gregg arrived, he was presented with a severely undersized and underweight roster composed mostly of freshmen. Gregg was taller and heavier than nearly the entire 70-man squad. The team was so short on offensive linemen that Gregg had to make several wide receivers bulk up and switch to the line. By nearly all accounts, it would have been unthinkable for the Mustangs to attempt to play the 1988 season under such conditions.
In 1989, the Mustangs went 2–9, including a 95–21 thrashing by Houston—the second-worst loss in school history. During that game, eventual Heisman Trophy winner Andre Ware threw six touchdown passes against SMU in the first half, and David Klingler added four more in the second half, even with the game long out of reach. Gregg was so disgusted that he refused to shake Houston coach Jack Pardee's hand after the game. Nonetheless, Gregg still looks fondly on the experience. In a 2012 interview with The New York Times, he said that the players on the two teams he coached should have had their numbers retired for restoring dignity to the program. "I never coached a group of kids that had more courage," he said. "They thought that they could play with anyone. They were quality people. It was one of the most pleasurable experiences in my football life. Period."
After the season, he was named athletic director. The Mustangs went 1–10 in 1990, and after the season Gregg resigned as coach to focus on his duties as athletic director. Gregg's coaching record at SMU was 3 wins and 19 losses, and he served as athletic director until 1994.