Vaccarella first contested the Targa Florio in 1959 in a privately entered Maserati, and returned the following year partnered with Umberto Maglioli in a birdcage Maserati for the Camoradi team. The car retired while leading, but the experience fired his ambition in the event.
His international profile grew steadily through the early 1960s. In 1963 he crashed a works Ferrari 250P in practice at the Nürburgring 1000km, breaking his arm, but came back to win the race the following year alongside Ludovico Scarfiotti. That victory set the stage for his greatest achievement: in 1964 he and Jean Guichet won the 24 Hours of Le Mans for Ferrari, claiming the pinnacle of long-distance racing.
His connection to the Targa Florio reached its fullest expression in 1965, when he and Lorenzo Bandini won at an average speed of 63.7 miles per hour, completing the race in 7 hours, 1 minute, and 12.4 seconds. He won the event a second time in 1971, sharing an Alfa Romeo with Toine Hezemans and finishing over a minute ahead of the nearest pursuer, ending a run of five consecutive Porsche victories at the race. His third Targa win came in 1975 with an Alfa Romeo 33TT12, by which point the event had left the World Sportscar Championship and become an Italian national race. After that victory, Vaccarella retired from racing, citing the desire to be present for his son Giovanni, born in 1972, during an especially dangerous era of motorsport.
Vaccarella was also active in North American endurance events. He qualified eighth for the 1970 24 Hours of Daytona in a Ferrari 512S and won the 1970 12 Hours of Sebring after Mario Andretti joined his car and delivered a decisive stint alongside Ignazio Giunti.
Vaccarella was selected for the 1962 Ferrari Formula One team by Enzo Ferrari, racing alongside John Surtees, Mike Parkes, Willy Mairesse, Lorenzo Bandini, and Ludovico Scarfiotti. He participated in five World Championship Grands Prix, debuting on 10 September 1961, without scoring championship points. He also contested several non-championship Formula One races during the same period.
Despite describing himself in later interviews as preferring fast circuits such as Le Mans, Monza, and Spa over slower road circuits, Vaccarella's identity in motorsport history is inseparable from the Targa Florio. Vic Elford captured the view of contemporaries: "He knew the roads on Sicily like the back of his hand." His three Targa victories, bracketing the golden years of the event, and his Le Mans win with Ferrari mark him as one of the most accomplished Italian drivers of the 1960s endurance era. He died on 23 September 2021 at the age of 88.