Renfro attended the University of Oregon, where he excelled as a track star and All-American halfback. In his four seasons with the Ducks, Renfro rushed for 1,532 yards and scored 141 points. As a track star for track coach Bill Bowerman Renfro was part of a World Record setting 440 yard relay team in 1962, with a time of 40.0 seconds. His running mates were Jerry Tarr, Mike Gaechter, and Harry Jerome. In 1986, Renfro was enshrined in the College Football Hall of Fame.
Mel Renfro is a member of The Pigskin Club of Washington, D.C. National Intercollegiate All-American Football Players Honor Roll.
Renfro was drafted by the Cowboys in the second round of the 1964 NFL Draft. He was initially placed as a safety, but was switched to cornerback in his fifth season. The speedy Renfro (4.65 40-yd dash) became an exceptional threat to wide receivers. Mel led the NFL with 10 interceptions in 1969. Renfro was selected to the Pro Bowl in each of his first ten seasons in the League, including five All-Pro selections in 1964, 1965, 1969, 1971, and 1973. Mel also was a significant threat on special teams, performing punt and kickoff return duties in addition to playing on defense, leading the league in punt and kickoff return yardage in 1964.
In his fourteen seasons, Renfro intercepted 52 passes, returning them for 626 yards and 3 touchdowns. He also returned 109 punts for 842 yards and 1 touchdown, 85 kickoffs for 2,246 yards and 2 touchdowns, along with recording 13 fumble recoveries, which he returned for 44 yards. In the 1970 NFC title game, Renfro had a key interception that led to the Cowboys' game-winning touchdown over the San Francisco 49ers that helped them get to Super Bowl V, where they lost to the Baltimore Colts. He would later play in Super Bowls VI, X and XII, retiring after the the final one, a Cowboys victory over the Denver Broncos.