McDuffie grew up in Sanford, North Carolina, and attended his first race at Bowman Gray Stadium at the age of ten, where drivers such as Curtis Turner, Glen Wood, and Billy Myers inspired him to pursue racing. He began on dirt tracks and won several small races across the Carolinas, including a track championship at a small dirt track near Rockingham, North Carolina.
He made his NASCAR Grand National debut in 1963 at Myrtle Beach Speedway, driving Curtis Turner's old 1961 Ford. Though he was an accomplished dirt track racer, that success did not translate to sustained results in NASCAR's premier series.
McDuffie ran as a low-budget independent for virtually his entire career, funding his operation without major sponsorship or factory support. Despite the financial disadvantages, he made 653 starts in NASCAR's top series — ranking 22nd all-time through the end of 2018 — and collected 106 top-ten finishes. He also held the record for the most last-place finishes in the series with 32, a total later surpassed by Joe Nemechek in 2014.
His best finishing result came in 1971 at the Albany-Saratoga Speedway, where he finished third. His only career pole position came in 1978 at the Delaware 500. In 1982, he made a start at the season-ending race at Riverside in Junior Johnson's second car, an entry arranged to protect Darrell Waltrip's championship campaign: if Waltrip suffered a practice or qualifying incident, McDuffie would relinquish the car to him.
In the 1988 Daytona 500 qualifying race, McDuffie suffered second- and third-degree burns in an accident after his fireproof gloves were stolen before the race.
On August 11, 1991, on the fifth lap of the Budweiser at The Glen, McDuffie's left front wheel spindle broke at approximately 170 mph on the straight between the esses and the loop-chute section. The mechanical failure caused him to lose both brakes and steering control. He struck Jimmy Means's car in the right front and, with no gravel trap in the corner, skidded across the grass and hit the Armco retaining wall and tire barrier with severe force. The car rebounded into the air, rotated 180 degrees, and came to rest upside-down. Means escaped with minor cuts and bruises. McDuffie died instantly from head and brain injuries — a basilar skull fracture later determined by accident investigators to have been caused by a tire from the barrier entering the cockpit through the passenger window.
The race was red-flagged for nearly two hours. NASCAR declined to investigate the accident in depth, and McDuffie's car was removed from the track before the race concluded. The cause of the wheel spindle failure was never officially explained.
McDuffie's death contributed directly to motorsport safety advancements. His fatal injury type — basilar skull fracture from rapid head movement — became a focus of ongoing research by Jim Downing and Bob Hubbard into head and neck restraints. Their work led to the HANS device, which had just entered production at the time of McDuffie's death. His accident was one of the catalysts for accelerated funding and adoption of HANS technology, which was eventually mandated by most major sanctioning bodies worldwide. NASCAR required HANS devices for all drivers beginning in October 2001, more than a decade after McDuffie's death.
Watkins Glen International installed a bus stop chicane and a gravel trap at the accident site for the 1992 season. McDuffie's widow, Ima Jean, filed a $4.25 million wrongful death lawsuit against the circuit; the presiding judge ruled against her, finding that McDuffie was aware of the track's dangers and that mechanical failure had caused the accident.
McDuffie is buried at Buffalo Cemetery in Sanford, North Carolina. The city of Sanford, which had long supported him through the financial struggles of independent racing, considered him a hometown figure of enduring significance. In 2016, Front Row Motorsports honored McDuffie with a tribute paint scheme during the throwback weekend at Darlington Raceway.