Vincenzo Florio had already founded the Coppa Florio race in Brescia in 1900. The Targa, named for its distinctive plaque (targa) awarded to the winner, was conceived as an even more ambitious event on Sicilian roads. The inaugural 1906 race was run over three laps of a 148 km circuit, totalling 444 km of winding mountain roads with around 2,000 corners per lap and over 1,100 metres of elevation change. Alessandro Cagno won the first edition in nine hours at an average of 30 miles per hour.
The course was progressively shortened over subsequent years. By the early 1920s it had been reduced to 108 km, and after 1932 it was run on the 72 km Piccolo delle Madonie circuit — a change made possible by a road connecting Caltavuturo and Collesano built at the direct order of Benito Mussolini at Florio's request. A special one-off return to the 146 km Grande course was made in 1931 after landslides destroyed roads unique to the intermediate Medio layout.
Through the early to mid-1920s the Targa Florio was one of Europe's most important races, filling the vacuum left by the fact that neither the 24 Hours of Le Mans nor the Mille Miglia had yet been established. The 1924 victory by German driver Christian Werner in a Mercedes — the first non-Italian winner since 1920 — made a strong impression in Germany and helped cement the international prestige of the event. In 1927, Eliska Junkova became the first woman ever to compete in the Targa Florio, marking her place in Grand Prix motor racing history.
Tazio Nuvolari won the 1932 Targa Florio, the last edition fully organised by Vincenzo Florio himself. By 1933, Florio had been ousted by the political machinations of the auto club, and the race began to decline. The mixture of Grand Prix cars and sportscars that had characterised the Targa became increasingly difficult to sustain as single-seat Grand Prix machinery evolved under the new AIACR European Championship, and German Silver Arrows manufacturers focused their attention on faster, higher-profile venues.
The 1935 race, won by an Alfa Romeo P3 Type B Grand Prix car, proved to be the final Targa Florio contested over a mountain road circuit in the pre-war era. In 1936 the club was barely able to organise a race at all; a handful of amateur entrants completed two laps of the Piccolo course in touring cars, a result that existed mainly to preserve an entry in the history books for that year. From 1937 to 1940, the event moved to a closed circuit in the Favorita Park in Palermo, contested by the Voiturette class for 1,500 cc cars. The Maserati 6CM dominated these Palermo editions, with Luigi Villoresi winning the last two rounds in 1939 and 1940. By 1941 even the Floriopolis pit facilities had been dismantled.
The pre-war Targa Florio shaped the identity of the race that would later become a pillar of the post-war World Sportscar Championship between 1955 and 1973. Its extraordinary difficulty — the punishing combination of thousands of corners, severe elevation changes, and public roads that competitors had to learn in open traffic — created a racing culture unlike any other event in the world. Porsche eventually named the hardtop-convertible variant of their 911 after the Targa in recognition of the marque's post-war success at the event.