Born in Rome, Musso began racing in sportscar competition before turning his attention to Formula One. His early years on track built the technical foundation for a career that would place him among Italy's leading drivers of the 1950s.
Musso made his Formula One debut in 1953 at the Italian Grand Prix with Maserati. In 1954 he won the Coppa Acerbo, a non-championship Formula One race, and finished second at the Spanish Grand Prix to score his maiden championship podium. Racing full-time for Maserati in 1955, he repeated his podium form at the Dutch Grand Prix at Zandvoort.
At the end of 1955 Musso moved to Ferrari, joining one of the sport's most competitive environments. On his Ferrari debut at the 1956 Argentine Grand Prix, he won the race in a shared drive with Juan Manuel Fangio, completing 30 of the 98 laps. It was his sole World Championship victory. His 1956 season was cut short after a crash in a sportscar race at the Nürburgring.
Musso's time at Ferrari was marked by a tense rivalry with British teammates Mike Hawthorn and Peter Collins. Fiamma Breschi, Musso's girlfriend at the time of his death, later revealed in a television documentary that Hawthorn and Collins had an informal financial arrangement — whichever of the two won, they would split the prize money equally — effectively presenting a united front against Musso. Breschi described this as fuelling a competitive antagonism that pushed all three drivers to take greater risks on track. She also disclosed that at the time of his death, Musso was burdened by significant personal debts, giving him particular motivation to win the 1958 French Grand Prix, which traditionally carried the largest monetary prize of the season.
Musso enjoyed a strong 1957 campaign. He won the Grand Prix de la Marne, a non-championship race, and finished third in the overall World Drivers' Championship standings behind Fangio and his Ferrari teammate Brooks. In sportscar competition he won the 1000 km Buenos Aires with Ferrari as part of the World Sportscar Championship, and the city race on 20 January 1957 with a Ferrari 290 MM.
In 1958 Musso claimed victory at the Targa Florio alongside Olivier Gendebien in a Ferrari Testa Rossa, one of the most celebrated victories of his career. He also participated in the second Race of Two Worlds at Monza, sharing a Ferrari 412 MI with Phil Hill and Mike Hawthorn, where the car finished third against purpose-built American oval machines.
During the 1958 French Grand Prix at Reims, Musso was chasing race leader Mike Hawthorn on the tenth lap of a 50-lap race. His Ferrari 246 ran wide at the Gueux Curve, struck a ditch, and somersaulted. Musso was airlifted to hospital with critical head injuries and died later that day on 6 July 1958. He was 33 years old. Hawthorn went on to win the race.
Within a year of Musso's death, both Peter Collins and Mike Hawthorn were also dead — Collins killed at the German Grand Prix later in 1958, Hawthorn in a road accident in January 1959. Fiamma Breschi said that the deaths of Hawthorn and Collins brought her a form of peace, having harboured lasting resentment over their treatment of Musso and their reaction to his crash.
Musso is remembered as one of the finest Italian Formula One drivers of the 1950s and among the most talented of a generation defined as much by loss as by achievement. His one championship win, taken on the biggest stage alongside the great Juan Manuel Fangio, stands as the high point of a career that might have yielded considerably more had the risks of 1950s motor racing not claimed him at 33.