Meredith played his college football at Southern Methodist University, where he started at quarterback for 3 years, leading the Southwest Conference in passing completion percentage each year and getting selected as an All-American in 1958 and 1959.

The Chicago Bears chose Meredith in the third round of the 1960 NFL draft, and traded him to a young Cowboys franchise for future draft picks. Meredith spent five years as a backup to Eddie LeBaron before he was given the starting job by head coach Tom Landry in 1965. That same year, Meredith led the Cowboys to the NFL playoffs, something he would continue to do until his unexpected retirement in 1969.

"Dandy Don", while never leading the Cowboys to an NFL Championship or a Super Bowl, has always been 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.

During his career, he had a 50.7% completion rate, throwing for 17,199 yards and 135 touchdowns with a lifetime quarterback rating of 74.8. He was named the NFL Player of the Year in 1966 and was named to the Pro Bowl twice.

Following his football career,  Don Meredith became a color commentator for ABC's Monday Night Football beginning in 1970. He left for three seasons (1974 to 1976) to work with Curt Gowdy at NBC, then returned to MNF partners Frank Gifford and Howard Cosell. His approach to color commentary was light-hearted and folksy, in contrast to Cosell's detailed and intellectual analysis and Gifford's rather pondorous play-by-play technique. He was known for singing "Turn out the lights, the party's over" at the time the game was apparently decided. Meredith retired from sportscasting after the 1984 season, a year after Cosell's retirement.

Meredith also had an acting career, appearing in multiple movies and television shows.

In 1976, Meredith was inducted into the Cowboys' Ring of Honor at Texas Stadium along with former running back Don Perkins.