Isaac grew up on a farm near Catawba, North Carolina, the second-youngest of nine children. He left school after the sixth grade, a fact that spawned an incorrect rumour that he could neither read nor write. He began racing full-time in 1956 but spent seven years working his way up before breaking into the Grand National division.
Isaac's partnership with car owner Nord Krauskopf and crew chief Harry Hyde produced some of the most dominant results of the late 1960s and early 1970s. In 1969 he set a NASCAR record that still stands: 20 pole positions in a single season. The following year he converted that qualifying speed into the 1970 Grand National championship, winning eleven races in the No. 71 Dodge Charger Daytona sponsored by K&K Insurance. Over his career he won 37 races in NASCAR's top series and started from the pole 49 times.
His speed extended beyond race weekends. In November 1970, Isaac took the No. 71 Dodge to Talladega Superspeedway and recorded a lap of 201.104 mph, a closed-course record that stood until 1983. In September 1971, he traveled to the Bonneville Salt Flats in Utah and set 28 world land speed records, several of which remained on the books for decades afterward.
Isaac's most talked-about moment came not from a victory but from a sudden, unexplained retirement during the 1973 Talladega 500. Running competitively, he simply drove to the pits and stopped. "I wasn't afraid I was going to wreck," he said afterward. "I don't have anything to prove to myself or to anybody else. I know how it feels to win and lose. I know how it feels to be a champion. And now I know how it feels to quit. It just entered my mind at that moment." His team owner had no warning; the decision was apparently instantaneous. Isaac did not contest any further Winston Cup races that season, and most observers assumed he was retiring from the sport entirely.
A later account from friend and former driver Ned Jarrett suggested Isaac had "heard a voice" instructing him to stop, connecting the moment to the death of Larry Smith in the same race — the first fatality at Talladega Superspeedway. Isaac did return to NASCAR from 1974 through 1976 on a reduced schedule, but he never recaptured his championship-level form.
On the night of August 13, 1977, Isaac was running fourth in the Winston 200 late model sportsman race at Hickory Motor Speedway when he pulled out of the race with 40 laps remaining and called for a relief driver. He collapsed on pit road, apparently from heat exhaustion during conditions that had peaked at 91 °F that afternoon. Revived briefly at the hospital, he died of a heart attack caused by the heat exhaustion at 12:45 a.m. on August 14, 1977 — thirteen days after his 45th birthday.
Isaac was inducted into the National Motorsports Press Association Hall of Fame in 1979, the International Motorsports Hall of Fame in 1996, and the NASCAR Hall of Fame in 2016. His single-season pole record of 20 in 1969 and the longevity of his Talladega closed-course speed record testify to a driver whose outright pace was rarely matched in the stock car era. The abruptness of his 1973 Talladega withdrawal remains one of NASCAR's most discussed unsolved episodes.