After serving in World War II, Lewis played basketball for the University of Houston until his graduation in 1947. He became an assistant coach there in 1953, and head coach in 1956. As a coach, he was known for championing the once-outlawed dunk, which he characterized as a “high percentage shot”, and for clutching a brightly colored red-and-white polka dot towel on the bench during games. Lewis was a major force in the racial integration of college athletics in the South during the 1960s, being one of the first major college coaches in the region to actively recruit African-American athletes. His recruitment of Elvin Hayes and Don Chaney in 1964 ushered in an era of tremendous success in Cougar basketball. The dominant play of Hayes led the Cougars to two Final Fours and sent shock waves through Southern colleges that realized that they would have to begin recruiting black players if they wanted to compete with integrated teams.
Lewis led the Houston Cougars program to 27 straight winning seasons, 14 seasons with 20 or more wins, and 14 trips to the NCAA Tournament. His Houston teams advanced to the Final Four on five occasions (1967, 1968, 1982–1984) and twice advanced to the NCAA Championship Game (1983, 1984). Among the outstanding players who Lewis coached are Elvin Hayes, Hakeem Olajuwon, Clyde Drexler, Otis Birdsong, Dwight Jones, Don Chaney, and Louis Dunbar.
Lewis’s Houston teams twice played a role in events that helped to popularize college basketball as a spectator sport. In 1968, his underdog, Elvin Hayes-led Cougars upset the undefeated and top-ranked UCLA Bruins in front of more than 50,000 fans at the Houston Astrodome. This was the first nationally televised college basketball game, and subsequently became known as the “Game of the Century”. It marked a watershed in the emerging popularity of college basketball. In the early 1980s, Lewis’s Phi Slama Jama teams at UH gained notoriety for their fast-breaking, “above the rim” style of play as well as their overall success. At the height of Phi Slama Jama’s notoriety, they suffered a dramatic, last-second loss in the 1983 NCAA Final that became an iconic moment in the history of the sport. Lewis’s insistence that his teams play an acrobatic, up-tempo brand of basketball that emphasized dunking brought this style of play to the fore and helped popularize it amongst younger players.
The Cougars also lost in the 1984 NCAA Final to the Georgetown Hoyas led by Patrick Ewing. Lewis retired from coaching in 1986 at number 20 in all-time NCAA Division I victories, his 592–279 record giving him a .680 career winning percentage. In 1995, the University of Houston modified the official name of the on-campus basketball arena to “Guy V. Lewis Court at Hofheinz Pavilion” in honor of Lewis, making him a university namesake.