Towne wrote the screenplay for the Corman-financed Last Woman on Earth (1960), in which he also played the lead role.

The following year he also starred in the Corman-financed Creature from the Haunted Sea (1961).

He also wrote a screenplay for the Corman-directed The Tomb of Ligeia (1965).

Towne was asked to help out on the script for Bonnie and Clyde (1967). The film was a huge success and although Towne's contribution was only "special consultant", he began to earn a reputation in Hollywood as a top "script doctor"

Towne was credited on Villa Rides (1968) and did uncredited work on Drive, He Said (1971), Cisco Pike (1972), The New Centurions (1972), The Godfather (1972) and The Parallax View (1974).

Towne received great acclaim for his film scripts The Last Detail (1973), Chinatown (1974), and Shampoo (1975). He was nominated for an Oscar for all three scripts, winning for Chinatown.

Towne was credited for his work on The Yakuza (1975) and did script doctoring on The Missouri Breaks (1976), Orca (1977) and Heaven Can Wait (1978).

Towne turned to directing with Personal Best (1982). He also wrote the script for Greystoke: The Legend of Tarzan, Lord of the Apes, hoping to direct, but Personal Best was a financial failure, meaning he had to sell the Greystoke script. He grew dissatisfied with the production and credited his dog, P.H. Vazak, with the script. Vazak became the first dog nominated for an Oscar for screenwriting, but he did not fetch the award.

Towne did uncredited work on Deal of the Century (1983), 8 Million Ways to Die (1986) (), Tough Guys Don't Dance (1987) and Frantic (1988).

His second feature film as Director was Tequila Sunrise (1988). Towne told The New York Times that Tequila Sunrise is "a movie about the use and abuse of friendship."

Towne wrote the script for Days of Thunder (1990) and formed a close relationship with its star Tom Cruise.

He was one of the Writers on Cruise's The Firm (1993), then Beatty's Love Affair (1994). Cruise brought him on to Mission: Impossible (1996) and co produced Towne's third film as Director, Without Limits (1998). He also co-wrote Mission Impossible II (2000) for Cruise.

In 2006, Towne was the subject of Artist Sarah Morris's film, Robert Towne. Morris describes him as an “elliptical figure” whose career exemplifies a certain characteristic mode of working in the film industry, marked by collaboration, shared or changing roles. Morris's 19,744-square-foot (1,834.3 m) painting installation in the lobby of the Lever House in Manhattan, commissioned by the Public Art Fund, was also titled "Robert Towne".

In a November 5, 2007 interview with MTV, Jack Nicholson claimed that Towne had written the part of Gittes specifically for him. In the same interview, Nicholson also said that Towne had conceived Chinatown as a trilogy, with the third film set in 1968 and dealing in some way with Howard Hughes. However, Towne says he "does not know how that got started" and denies there was any trilogy planned.

In 2008, Towne was the subject of the documentary short film "Robert Towne", by Artist Sarah Morris.

In 2011, Towne was announced as writer-director of The 39 Steps, a proposed remake of the 1935 film directed by Alfred Hitchcock. The British Producer Graham King revealed that he had hired Towne to write a remake of The Battle of Britain in a December 2011 interview.

Robert Towne expressed his disappointment in The Two Jakes in many interviews. He told Writer Alex Simon "In the interest of maintaining my friendships with Jack Nicholson and Robert Evans, I’d rather not go into it, but let’s just say The Two Jakes wasn’t a pleasant experience for any of us. But, we’re all still friends, and that’s what matters most."