Meredith spent two years as a backup to Eddie LeBaron, eventually splitting time in 1962 before he was given the full-time starting job by head coach Tom Landry in 1963. In 1966, Meredith led the Cowboys to the NFL postseason, something he would continue to do until his unexpected retirement before the 1969 season. His two most heartbreaking defeats came in NFL Championship play against the Green Bay Packers, 34–27 in Dallas (1966), and the famous "Ice Bowl" game, 21–17 in Green Bay (1967).
"Dandy Don," while never leading the Cowboys to a Super Bowl, was always exceptionally popular with Cowboys fans who remember him for his grit and toughness, his outgoing nature, and his leadership during the first winning seasons for the Cowboys. Meredith, along with Harvey Martin, is among the few players to play his high school (Mount Vernon), college (SMU), and pro (Dallas Cowboys) career in and around the Dallas, Texas, area. During his career, he had a 50.7 percent completion rate, throwing for 17,199 yards and 135 touchdowns with a lifetime passer rating of 74.8. He was named the NFL Player of the Year in 1966 and was named to the Pro Bowl 3 times. According to the NFL, the longest pass with no Yards After Catch (YAC) was an 83 yard pass from Don Meredith to Bob Hays. However, the NFL does not keep statistics on the distance of actual passes
Meredith also had an acting career, appearing in multiple movies and television shows, including a recurring starring role as Detective Bert Jameson on Police Story. One episode, "The Witness," features a picture of Don in his Dallas uniform hanging on a wall in Delaney's bar while Don interviews witnesses to a robbery below his picture. He was in a series of commercials in the 1980s as Lipton Tea Lover, Don Meredith, a.k.a. "Jeff and Hazel's Baby Boy". He was featured in an episode of King of the Hill, ("A Beer Can Named Desire") in which he misses a throw that would have won the main character, Hank Hill, $100,000.00.
Former Dallas Cowboy wide receiver, and Meredith teammate Peter Gent's novel North Dallas Forty is a fictional account of life in the NFL during the 1960s featuring quarterback Seth Maxwell, a character widely believed to be based on Meredith and receiver Phil Elliot, believed to be based on Gent. Maxwell and Elliot are characterized as boozing, womanizing, ageing stars in the twilight of their careers held together by pills and alcohol. Of the story, Meredith said, "If I'd known Gent was as good as he says he was, I would have thrown to him more."
Meredith was married three times: first wife, Lynne Shamburger, a former SMU cheerleader, which lasted from 1959–63, and had one daughter, Mary. From 1965–71, he was married to the former Cheryl King, through whom he had two more children, son Michael and daughter Heather. He met his third wife, the former Susan Lessons Dullea, ex-wife of actor Keir Dullea, as they both were walking down 3rd Avenue in New York City. They married in 1972.