He played college football for the SMU Mustangs, and was selected by the Chicago Bears 32nd overall in the 1960 NFL Draft, which took place in November 1959.

[4] Although he was heavily recruited by Texas A&M head coach Bear Bryant,[4] Meredith played college football at Southern Methodist University (SMU) in Dallas.

[5] He led the Southwest Conference (SWC) in passing completion percentage in each of his three years as the starting quarterback (1957–59), and was an All-America selection in 1958 and 1959.

[7] He completed 8 of 20 passes for 156 yards in the College All-Stars' 32–7 loss to the defending NFL champion Baltimore Colts in Chicago on August 12, 1960.

[8][9][10] Meredith was honored twice by SMU in later decades; he was the recipient of the university's Distinguished Alumni Award in 1983, and his jersey number 17 was retired during halftime ceremonies at the SMU–Houston game on October 18, 2008.

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.

Already feeling physically and mentally fatigued as a leader, he had his worst playoff outing in 1968 against the Cleveland Browns in the Eastern Conference Championship game, throwing three interceptions before being benched, which led to his retirement in 1969 at age 31.

Following his football career, Meredith helped market Docutel automated teller machines; his brother B. J. was president of the Dallas-area company.

He left for three seasons (1974–1976) to work with Curt Gowdy at NFL on 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 scholarly, professorial observations and Gifford's straightforward, technical play-by-play analyses.

Meredith's broadcasting career was also not without a few incidents of minor controversy, including referring to then-President Richard Nixon as "Tricky Dick", announcing that he was "mile-high" before a game in Denver, and turning the name of Cleveland Browns receiver Fair Hooker into a double entendre (saying "Fair Hooker...well, I haven't met one yet!").

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

The novel North Dallas Forty, written by former Dallas Cowboy wide receiver and Meredith teammate Peter Gent, 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.

He was also part of an ensemble cast in his son Michael Meredith's Three Days of Rain with Blythe Danner, Peter Falk, and Jason Patric.

Meredith died on December 5, 2010, at St. Vincent Regional Medical Center in Santa Fe, New Mexico, after suffering a brain hemorrhage.