Garlits built his first race car in 1954 under an oak tree at his North Tampa home, fashioning a T-Bucket from a 1927 Ford Model T Roadster fitted with a 1948 Mercury engine block. That homemade machine ran 13.5 seconds at 93 mph before he stripped it down and converted it into a slingshot rail dragster — the configuration he would ride to his first NHRA win, at the NHRA Safety Safari in Lake City, Florida. Being from Florida placed him outside the dominant California drag racing scene, earning him the nickname "Swamp Rat," which he subsequently gave to every new generation of his dragster designs.
In 1959, Garlits drove to Bakersfield, California for the US Fuel and Gas Championships, attracting over 30,000 spectators — the largest drag racing crowd to that point — and helping expand the sport beyond its West Coast base. A 1964 trip to England for the first International Drag Festival further spread drag racing internationally.
On March 8, 1970, at Lions Drag Strip, the transmission of Swamp Rat XIII exploded during a run, severing part of Garlits's right foot and splitting the car in two. Rather than return to the same front-engine slingshot layout that had injured him, Garlits designed an entirely new configuration from his wheelchair in his Seffner, Florida shop.
In 1971 he debuted Swamp Rat XIV — a mid-engined, front-cockpit rail dragster that placed the driver ahead of the engine and fuel systems. The rodding press was skeptical, and Garlits lost his first outing with the new car. But the design quickly proved its worth: he won two of his next three Top Fuel Eliminator titles that season, at the Winternats and Bakersfield. Within a few years, rear-engine dragsters became the universal standard in Top Fuel competition and remain so to this day.
Across his career, Garlits accumulated 17 major sanctioning body championships: ten American Hot Rod Association titles, four International Hot Rod Association championships, and three National Hot Rod Association championships — the last claimed when he was 54 years old. He won 144 national events in total.
After a blowover crash at the 1987 AHRA World Finals in Spokane, Washington, he temporarily retired from driving and served as a color commentator for NHRA telecasts on TNN and NBC from 1988 through 1991. He came out of retirement in December 1991 for the Snowbird Nationals, then retired again before the end of the 1992 season due to a detached retina caused by the deceleration forces produced by a dragster's braking parachutes.
Garlits made further comebacks in 1998 and 2003. His final qualifying appearance came in May 2003 at the NHRA Southern Nationals in Atlanta, where at age 71 he set a personal best quarter-mile time of 4.788 seconds at 319.98 mph.
Garlits pursued performance innovation into his eighties. In May 2014, at age 82, he drove Swamp Rat 37 — a 2,000 hp battery-powered electric dragster — to a speed of 184 mph, setting an EV land speed record. In July 2019, at age 87, he piloted Swamp Rat 38 to 189.03 mph, establishing a new quarter-mile record for electric dragsters.
Garlits's influence on drag racing extends well beyond his driving record. His promotion of rear-engine design eliminated one of the most lethal failure modes in the sport, and his early advocacy for full Nomex driving suits, gloves, socks, and balaclava helped establish fireproof gear as standard equipment.
His dragster Swamp Rat XXX was enshrined in the National Museum of American History at the Smithsonian Institution in Washington, D.C. in October 1987. The National Hot Rod Association ranked him first on its Top 50 Drivers list (1951–2000). He was inducted into the Motorsports Hall of Fame of America in 1989, the International Motorsports Hall of Fame in 1997, and the Automotive Hall of Fame in 2004. In 2008 ESPN ranked him 23rd among the greatest drivers of all time. He was also inducted into the British Drag Racing Hall of Fame in 2014 as its Overseas Member.
Garlits operates the Don Garlits Museum of Drag Racing in Ocala, Florida, where he has also mentored current Top Fuel racer Josh Hart.