Mel was born on December 30, 1941 in Houston, Texas. After graduating high school in Portland, Oregon he attended the University of Oregon, where he excelled as a track star and as a two-way football player, an All-American halfback and defensive back. In his three seasons with the Ducks, Renfro rushed for 1,532 yards and scored 141 points.
One of Renfro's best collegiate games took place against Rice University at Houston in 1962. Renfro shined on both offense and defense, leading the Ducks to a 31-12 victory. Rice Stadium had been a whites-only facility prior to the Ducks' visit, but university officials allowed Renfro's family to enter and sit in a special section of the stadium near the 35-yard line. According to a contemporary account in the Eugene (Ore.) Register-Guard, when Renfro left the game, he was given a loud and appreciative ovation by the Rice crowd. An Oregon sportswriter asked a Houston counterpart in the press box if an African-American had ever received such an ovation by a predominantly white crowd. The Texan enthusiastically replied, "We've never seen any player that good!" The morning after the game, a Houston paper headlined, "Renfro Runs Rice Ragged."
In 1986, Renfro was enshrined in the College Football Hall of Fame and is a member of The Pigskin Club of Washington, D.C., a National Intercollegiate All-American Football Players Honor Roll. As a track star at Oregon, Renfro was part of a world record-setting 440 yard relay team in 1962, with a time of 40.0 seconds.
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 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 final one, a Cowboys victory over the Denver Broncos.
Renfro was added to the Texas Stadium Ring of Honor in 1981, and was elected to the Pro Football Hall of Fame in 1996.