Billy Cannon started high school at Istrouma in Baton Rouge, in 1952. He was noted for his speed and strength, and became a star athlete in football and track. In football, he scored 39 touchdowns his senior year, was named All-State and All-America and led his high school to a state championship in 1955. He would later run the 100 yard dash in 9.4 seconds, and the 40 yard dash in 4.12 seconds. He put a 16-pound shot 54 feet.
Cannon played three seasons for LSU: 1957, 1958, and 1959. In 1958, Cannon led LSU to its first AP national championship. #1 LSU clinched the title in the Sugar Bowl, beating #12 Clemson 7-0. The only score was a pass from Cannon to Mickey Mangham. Cannon was also voted the 1958 UPI Player of the Year. On Halloween night 1959, Cannon led #1 LSU to a victory over #3 Ole Miss in Tiger Stadium. The Tigers were trailing 3-0 when Cannon returned a punt 89 yards for a TD, breaking seven tackles and running the last 60 yards untouched. It was the only TD of the game, resulting in a 7–3 victory. That year, Cannon won the Heisman Trophy and was again voted the UPI Player of the Year. Other big games from Cannon's time at LSU were unranked LSU's 20–13 victory over #17 Georgia Tech in 1957, #1 LSU's 14–0 victory over #6 Ole Miss in 1958, and #1 LSU's 10-0 victory over #9 TCU in 1959.
The No. 20 jersey worn by Cannon was retired after the 1959 season. It was the only football number retired by LSU until 2009, when Tommy Casanova received this honor.
Cannon had been originally elected to the College Football Hall of Fame in 1983, but the Hall rescinded the honor before his induction due to his confessed involvement in a counterfeiting scheme (for more information on the scheme, see below). The Hall elected him a second time in 2008, and he was formally inducted during a ceremony on December 9 of that year.
Cannon had an uncommon combination of brute strength with the speed of a sprinter. A track and field coach is reported to have remarked during his college career that he could have lost 15 pounds and won the NCAA title in the 100 meter dash, or gained 15 pounds and won the NCAA title in the shotput. In 1960, his signing by the Houston Oilers followed a fierce bidding war that began when Oilers owner Bud Adams met Cannon in the end zone following LSU's Sugar Bowl victory, and ended in court, with the AFL winning against the NFL. That put the fledgling league on the football map. Cannon, at halfback, scored an 88-yard touchdown on a pass from George Blanda in the first AFL Championship game, a 24-16 victory over the Los Angeles Chargers. He scored the only touchdown in the Oilers’ repeat victory over the San Diego Chargers in the second-ever AFL Championship game.
Cannon amassed 2,043 all-purpose yards in 1961, and led the league in rushing. He played for the Oilers from 1960 through 1963 and went to the Oakland Raiders in 1964. Al Davis converted him to tight end during the 1964 season, and he finished his career as one of the best players of all time at that position. Cannon was All-League in 1961 and played in the AFL All-Star Game as a halfback in 1961. He was an AFL All-League selection at tight end in 1967, when he scored 10 receiving touchdowns. He played tight end in the in 1969AFL All-Star Game. He accounted for a total of 64 touchdowns in his career, 47 of them receiving. For his career, he amassed 3,656 yards receiving, 2,455 yards rushing, and 1,882 return yards for a combined total of 8,003 yards and 63 touchdowns. He also passed for 46 yards and one touchdown. He played in a total of six AFL Championship games, winning twice with the Oilers and once with the Raiders.
Billy Cannon is one of 20 players who played the entire ten years of the American Football League's existence. He is also one of 14 players to score 5+ touchdowns in one game, and also holds the Oilers/Titans franchise record for most points (30) and most touchdowns (5) in a single game.
In 1995, he was hired as a dentist at the Louisiana State Penitentiary, initially as a contractor. At the time, the dental clinic in the prison was in chaos, with many dentists refusing to work and inmates often being unable to make appointments. Cannon immediately set to reorganizing the dental program with great success and was soon hired as a full-time employee. The warden, impressed with Cannon's work with the dental program, later put him in charge of the prison's entire medical system. Cannon remains the resident dentist at the penitentiary, where inmates typically call him "Legend".
Cannon resides in St. Francisville, Louisiana. On February 19, 2013, Cannon was hospitalized in intensive care in Baton Rouge after suffering a stroke. His family reported that he was alert and resting and that further tests would be conducted to determine the extent of his ailment.