Desperate to challenge the supercharged Alfas, Ferrari was open to trying something different. During the 1949 season, Enzo Ferrari grew increasingly impressed of the performance of the naturally aspirated, 4.5-litre engined Talbot Lagos. Although down on power compared to the supercharged Ferraris and Alfa Romeos, the French cars at times made up for it by needing less fuel stops and tyre changes.
Enzo Ferrari had seen enough during 1949 and commissioned new chief engineer Aurelio Lampredi to develop an altogether larger V12 engine. To distinguish it from Ferrari's original V12, designed by Gioacchino Colombo, the new Lampredi V12 has since been referred to as the 'long-block' engine. Like the short-block V12, Lampredi's new engine featured an alloy block and cylinder heads. A single overhead camshaft in each head, driven by gears from the crankshaft, operated two valves per cylinder. The long-block V12 was equipped with three, twin-choke Weber carburetors. The Lampredi-engined cars featured a steel tubular frame constructed around two large diameter side members.
Suspension at the front was through double wishbones, a transverse semi-elliptic leaf spring and Houdaille shock absorbers. The transverse leaf spring and Houdaille shock absorbers were also used at the rear but this time combined with a sophisticated De Dion axle. Large, hydraulic drum brakes were used on all four corners.
Still under development as the 1950 season got under way, the new 4.5-litre, 375 F1 was not ready until the Italian Grand Prix in September where it qualified a strong second in the hands of Alberto Ascari. During the race Ascari suffered engine trouble but was able to garner 2nd after taking over Dorino Serafini's car to Nino Farina's winning Alfa Romeo.
In 1951 the Ferrari's won three out of the first four non-championship races. Scoring a couple of podiums in the first four championship races it was in England at the British Grand Prix, the Ferrari in the famous words of Enzo Ferrari "killed its mother". Jose Froilan Gonzalez took the pole for the race in his 375 while his teammates Alberto Ascari and Luigi Villoresi started in fourth and fifth. Gonzalez showed what the 375 was truly capable of as he beat his countryman Juan-Manual Fangio's Alfa Romeo by almost a minute. Ascari suffered gear box trouble but Villoresi was able to bring his Ferrari 375 in third. With Alfa Romeo's imminent withdrawal from the sport and no real rival to Ferrari stepping up, the sport's governing body decided to run the 1952 World Championship for Formula 2 cars rendering the 375 F1 obsolete. A pair of modified 375s would compete in various Formula Libre events as Thin Wall Specials.