Prudhomme entered drag racing as a crewmember, working for "TV Tommy" Ivo on Ivo's twin-engined slingshot in 1960. By 1962, he had moved into driving as a partner in the Greer-Black-Prudhomme fuel digger, a car that compiled what was described as the best win record in NHRA history before Prudhomme made the transition to Funny Car. Early career stints included a seat in the B&M Tork Master-sponsored dragster, where he replaced Tom McEwen after McEwen departed.
Prudhomme became the first Funny Car driver to exceed 250 mph. He raced a Shelby Super Snake during the 1968 and 1969 seasons, powered by a Ford engine at a time when the Chrysler Hemi was dominant in the class. When Ford discontinued the program, he entered what became one of the most celebrated rivalries in drag racing history.
Around 1972, motorsports promoter Bob Kachler arranged a landmark sponsorship deal with the U.S. Army for Prudhomme's Funny Car. Artist Kenny Youngblood redesigned the "Snake" logo in red, white, and blue for the Army-backed cars, a partnership that ran through the most productive stretch of Prudhomme's driving career, during which he won four NHRA Funny Car championships.
Prudhomme's rivalry with Tom "The Mongoose" McEwen became one of the defining stories of drag racing in the early 1970s. Prudhomme raced a yellow 1970 Plymouth Barracuda while McEwen drove a red 1970 Plymouth Duster, and the pair engaged in high-profile match races that brought national attention to the sport. Mattel released Hot Wheels toy versions of both cars in 1970 — among the first major corporate sponsorship packages in drag racing — dramatically raising the profile of both drivers. The rivalry inspired the 2013 film Snake and Mongoose and was chronicled in Tom Madigan's book Snake vs. Mongoose: How a Rivalry Changed Drag Racing Forever. Prudhomme appeared in the film as a track employee.
Prudhomme retired from driving in 1994 to manage his own racing team. His team achieved significant success in Top Fuel, winning the NHRA Top Fuel championship in both 2002 and 2003 with driver Larry Dixon. In 2009, Dixon moved to the Al-Anabi Top Fuel Dragster and Spencer Massey took over the seat. When sponsorship ended at the close of the 2009 season, Prudhomme retired from active involvement in racing as a team owner. In 2019 he returned in a sponsorship role, backing the Montana Brand/John Force Racing Top Fuel dragster driven by Austin Prock.
Prudhomme was inducted into the Motorsports Hall of Fame of America in 1991 and into the International Motorsports Hall of Fame in 2000. His autobiography, Don "The Snake" Prudhomme: My Life Beyond the 1320, written with Elana Scherr, was published in 2020. Hal Higdon's earlier book Six Seconds to Glory documented Prudhomme's early career through the 1973 NHRA Nationals in Indianapolis.
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