Born in Osimo in the Marche region of central Italy, Fagioli was drawn to motorsport from boyhood. He began with hillclimbing and sports cars before entering Grand Prix racing in 1926. Joining Maserati in 1930, he quickly established himself as a top contender, winning the Coppa Ciano and the Circuit of Avellino Grand Prix. In 1931 he staged a famous battle with Louis Chiron at Monaco — losing narrowly — before winning the Autodromo Nazionale Monza race ahead of Chiron, Achille Varzi, and Tazio Nuvolari. He moved to Scuderia Ferrari's Alfa Romeo team for 1933, winning the Coppa Acerbo (snatching victory after Nuvolari retired while leading late), the Grand Prix du Comminges, and the Italian Grand Prix. The Coppa Acerbo win in particular earned him the nickname "Il ladro degli Abruzzi" — the Abruzzi Robber.
Mercedes signed Fagioli for 1934. His fiery temperament produced immediate friction: in his first race for the team, he abandoned his car after team manager Alfred Neubauer ordered him to cede victory to Manfred von Brauchitsch. Despite the rocky start, Fagioli won the Coppa Acerbo, the Italian Grand Prix (shared with Rudolf Caracciola), and the Spanish Grand Prix. In 1935, driving a Mercedes W25B, he won the Monaco Grand Prix, the AVUS race, and the Penya Rhin Grand Prix while finishing runner-up in the European Drivers' Championship. His relationship with Mercedes deteriorated as recurring clashes with Caracciola over team orders intensified, and he left at the end of 1936 to join Auto Union. By then, severe rheumatism was visibly affecting him; at the 1936 Coppa Acerbo he could walk only with a cane.
After World War II, Fagioli's health improved sufficiently for him to join Alfa Romeo's Formula One squad for the inaugural 1950 World Championship at age 52. Driving the 158/159 Alfetta, he scored five podium finishes in six races and entered the final round — the Italian Grand Prix — as one of three drivers in title contention. Teammate Giuseppe Farina ultimately won the championship; Fagioli finished third, with Fangio second.
In 1951, Fagioli and Fangio were entered together in the French Grand Prix. When Fangio's car developed engine problems, team management ordered Fagioli to hand over his healthy machine to Fangio so that the Argentine could continue. Fagioli took over Fangio's ailing car. Under the shared-drive rules of the era both drivers were classified jointly, and Fagioli was co-credited with the win — making him, at 53 years and 22 days, the oldest Formula One race winner in history. The humiliation of the forced handover reportedly prompted Fagioli to retire from Formula One immediately after the race.
For 1952, Fagioli signed with Lancia to contest sportscar races. During practice for the Monaco Grand Prix — that year run as a sportscar event — he crashed his Lancia Aurelia in the tunnel. His injuries were at first considered minor, but his condition worsened over the following days and he died in a Monte Carlo hospital three weeks later on 20 June 1952, his 54th birthday.
Fagioli's record of podium finishes in Formula One is remarkable: aside from the 1950 Monaco Grand Prix, where a first-lap pile-up forced him out, he reached the podium in every World Championship race he started. That gives him an 85.71% podium rate, second-highest in Formula One history. He also remains the only driver to have won a championship race in both the AIACR pre-war European Championship and the post-war World Drivers' Championship — a bridge between two eras of Grand Prix racing.