Prudhomme entered drag racing as a crewman, working for "TV Tommy" Ivo on Ivo's twin-engined slingshot in 1960. By 1962 he had become a partner in the Greer-Black-Prudhomme fuel dragster, which achieved what was described as the best win record in NHRA history. This early partnership established his reputation as a driver of rare ability and smoothness behind the wheel.
Following the dissolution of the partnership, Prudhomme eventually aligned with Tom McEwen. In 1965 he competed at the Hot Rod Magazine Championship Drag Races at Riverside, one of the era's landmark events, as both men were building toward the high-profile careers that would define the sport through the next two decades.
Prudhomme became the first Funny Car driver to exceed 250 mph (400 km/h), a milestone that underscored his status as one of the sport's technical frontiersmen. From 1968 to 1969 he raced a Shelby Super Snake powered by a Ford engine — an unusual choice in a class dominated by Chrysler Hemi power — before returning to more conventional equipment.
Around 1972, motorsports promoter Bob Kachler arranged a sponsorship agreement with the United States Army for Prudhomme's Funny Car, recognizing that a popular and successful racer could serve as an effective recruitment tool for the Army's outreach to young Americans. Artist Kenny Youngblood redesigned the Snake logo in patriotic red, white, and blue for the Army-sponsored cars. The arrangement coincided with the most productive phase of Prudhomme's competitive career, during which he captured his four NHRA Funny Car titles.
Prudhomme's rivalry with Tom "The Mongoose" McEwen became the most celebrated in drag racing history. The two drivers match-raced extensively, with Prudhomme's yellow 1970 Plymouth Barracuda facing McEwen's red 1970 Plymouth Duster across tracks nationwide. The rivalry gained significantly wider public exposure when Mattel released Hot Wheels toy versions of both cars in 1970, one of the first major corporate sponsorship packages in the sport. The exposure the Mattel deal brought helped establish drag racing as a mainstream American motorsport.
Prudhomme retired from driving in 1994 and transitioned to team ownership, fielding entries in the NHRA Top Fuel category. With driver Larry Dixon, Prudhomme's team won consecutive Top Fuel World Championships in 2002 and 2003. In 2009, Dixon departed for the Al-Anabi team and Spencer Massey took over the seat, but the loss of sponsorship at season's end led Prudhomme to close the team. He sponsored and built the Montana Brand / John Force Racing Top Fuel dragster driven by Austin Prock in the NHRA Mello Yello Drag Racing Series in 2019, maintaining a connection to the sport in an ownership and mentorship capacity.
Don Prudhomme's influence on drag racing extends well beyond his four championships. His early milestone of breaking the 250 mph barrier in Funny Car, his Army sponsorship that helped legitimize the sport commercially, and his iconic rivalry with Tom McEwen reshaped how drag racing was packaged and sold to American audiences. Inducted into the Motorsports Hall of Fame of America in 1991 and the International Motorsports Hall of Fame in 2000, Prudhomme is recognized across motorsport as one of the defining figures of twentieth-century drag racing. The 2013 film Snake and Mongoose dramatized his rivalry with McEwen and their mutual role in bringing the sport into the mainstream. Author Hal Higdon chronicled his early career in Six Seconds to Glory, while Prudhomme's own memoir Don "The Snake" Prudhomme: My Life Beyond the 1320 was published in 2020.