Vessels was the first pick of the Baltimore Colts in the first round of the 1953 NFL Draft, but did not join the Colts following the draft, electing instead to play with the Edmonton Eskimos of the then Western Interprovincial Football Union. During his rookie season in 1953, Vessels led the WIFU, the forerunner of the CFL Western Conference (later changed to Division) in rushing with 926 yards on 129 carries and with eight rushing touchdowns. He caught 20 passes for 310 yards and with one touchdown. Vessels also passed 393 yards on 30 attempts with 18 completions and 4 touchdown passes to having thrown only one interception and while on defence he snagged four interceptions.
Vessels became the first player to win the Schenley Award as the Canadian Rugby-Football Union's (CRU) Most Outstanding Player (the CFL did not come into existence until 1958). Vessels played only the one season in Canada. In 1956 he joined the NFL's Baltimore Colts, the team that had drafted him three years prior. That season, his only for the Colts, he had 11 receptions for 177 yards and a touchdown plus returned 16 kickoffs for 379 yards. Unfortunately, Vessels' professional career in the NFL was cut short by a leg injury.
After his football career, Vessels was employed for many years by The Mackle Company, one of Florida's leading developers. In the 1970s, he became involved in horse breeding and served on the Florida Pari-Mutuel Commission from 1976 to 1983, becoming its executive director. He was elected president of the National Association of State Racing Commissions in 1984 and served as director of the Florida division of Pari-Mutuel Wagering from 1987 to 1989.
In September 2003, Cleveland, Oklahoma renamed its high school football stadium "Billy Vessels Memorial Stadium" in honor of Vessels. In 2007, the University of Oklahoma, through the state's Centennial Celebration, awarded the Vessels Heisman statue to Cleveland, Oklahoma, where it sits across from Cleveland High School in front of the school's gymnasium and event center. OU replaced its statue, and those of its other Heisman winners, the next spring.