Taruffi began his sporting career on motorcycles, winning the premier-class 500cc European Championship in 1932 on a Norton. In 1937 he set a motorcycle land-speed record of 274.18 km/h (170.36 mph) on the Autostrada Serenissima, holding that record for 38 days. He also designed the Gilera Rondine and the record-breaking Cisitalia Tarf streamliner, and managed the Gilera motorcycle team throughout much of his career.
Taruffi drove in 18 World Championship Grands Prix for Alfa Romeo, Ferrari, Mercedes, Maserati, and Vanwall. His finest Formula One season was 1952, when driving a Ferrari he won the Swiss Grand Prix at Bremgarten from the front, with Rudolf Fischer's Ferrari second. He accumulated enough points across the season to finish third in the championship behind World Champion Alberto Ascari and Giuseppe Farina. Over six seasons he scored 41 championship points in total. He also participated in numerous non-championship Formula One events.
Taruffi's sportscar record was extensive. In November 1951 he won the Carrera Panamericana in Mexico co-driving with Luigi Chinetti, completing the course at an average of 87.6 mph. He won the 1954 Giro di Sicilia in a Lancia D24 and the 1955 Tour of Sicily in a Ferrari. He placed fifth overall at Sebring in 1955 alongside Harry Schell.
In 1957, Taruffi entered the Mille Miglia for the last time. Driving a Ferrari 315 S, he won the race — his only Mille Miglia victory after years of near-misses, including second-place finishes in 1938, 1939, and a retirement while leading in 1954. He announced his retirement upon winning, ending his racing career at age 50. The 1957 Mille Miglia was tragically marred by Alfonso de Portago's fatal tyre failure, which killed de Portago, his co-driver Edmund Nelson, and nine spectators — leading to the race's permanent cancellation.
In 1959 Taruffi authored The Technique of Motor Racing, a widely read instructional book. He also published commentary on fatal incidents in racing in a 1957 Saturday Evening Post article. In 1952 he patented a novel three-bodied racing car design featuring parallel torpedo-shaped chassis sections. A museum dedicated to his career, the Piero Taruffi Museum, is located in Bagnoregio, in the Viterbo province of central Italy. Taruffi was portrayed by American actor Patrick Dempsey in the 2023 biographical film Ferrari.
Piero Taruffi died in Rome on 12 January 1988, aged 81. He stands as one of the most versatile Italian motorsport figures of the 20th century — a motorcycle champion, Grand Prix winner, record-breaker, engineer, and author whose career spanned three decades of competition at the highest levels of the sport.