Honda entered Formula One as a constructor for the first time in the 1964 season at the German Grand Prix with Ronnie Bucknum at the wheel. 1965 saw the addition of Richie Ginther to the team, who scored Honda's first point at the Belgian Grand Prix, and Honda's first win at the Mexican Grand Prix. 1967 saw their next win at the Italian Grand Prix with John Surtees as their driver. In 1968, Jo Schlesser was killed in a Honda RA302 at the French Grand Prix. This racing tragedy, coupled with their commercial difficulties selling automobiles in the United States, prompted Honda to withdraw from all international motorsport that year.

After a learning year in 1965, Honda-powered Brabhams dominated the 1966 French Formula Two championship in the hands of Jack Brabham and Denny Hulme. As there was no European Championship that season, this was the top F2 championship that year. In the early 1980s Honda returned to F2, supplying engines to Ron Tauranac's Ralt team. Tauranac had designed the Brabham cars for their earlier involvement. They were again extremely successful. In a related exercise, John Judd's Engine Developments company produced a turbo "Brabham-Honda" engine for use in CART racing. It won only one race, in 1988 for Bobby Rahal at Pocono.

Honda returned to Formula One in 1983, initially with another Formula Two partner, the Spirit team, before switching abruptly to Williams in 1984. In the late 1980s and early 1990s, Honda powered cars won six consecutive Formula One Constructors Championships. WilliamsF1 won the crown in 1986 and 1987. Honda switched allegiance again in 1988. New partners Team McLaren won the title in 1988, 1989, 1990 and 1991. Honda withdrew from Formula One at the end of 1992, although the related Mugen-Honda company maintained a presence up to the end of 1999, winning four races with Ligier and Jordan Grand Prix.