His feature film debut, The Story of a Three-Day Pass (1967), was based on his own French-language novel La Permission and was shot in France, as it was difficult for a black American director to get work at the time.

In 1971, he released his best-known work, creating and starring in the film Sweet Sweetback's Baadasssss Song, considered one of the earliest and best-regarded examples of the blaxploitation genre.

His son, filmmaker and actor Mario Van Peebles, appeared in several of his works and portrayed him in the 2003 biographical film Baadasssss!.

His first book, The Big Heart, credited to Melvin Van, evolved from a small article and a series of photographs taken by Ruth Bernhard.

On the way to Europe, in New York City, he met Amos Vogel, founder of the avant-garde Cinema 16 who agreed to place two of Van Peebles's shorts in his rental catalog.

[5] Vogel screened Van Peebles's Three Pickup Men for Herrick at Cinema 16 on a program with City of Jazz in the spring of 1960 with Ralph Ellison leading a post-film discussion.

[6] When Vogel went to Paris shortly after, he brought Van Peebles's films to show Henri Langlois and Mary Meerson at the Cinémathèque Française.

Himes got him a job at the anti-authoritarian humor magazine Hara-kiri, where Van Peebles wrote a monthly column and eventually joined the editorial board.

[9] Roger Blin directed La Fête à Harlem with the Les Griots theatrical troupe for the Festival du jeune théâtre in Liège, Belgium in September 1964.

[10] Van Peebles made his first feature-length film, The Story of a Three-Day Pass (La Permission) (1968) based on a novel by the same title.

[11] Van Peebles's first[citation needed] Hollywood film was the 1970 Columbia Pictures comedy Watermelon Man, written by Herman Raucher.

Starring Godfrey Cambridge, the movie tells the story of a casually racist white man who suddenly wakes up black and finds himself alienated from his friends, family, and job.

[citation needed] After Watermelon Man, Van Peebles became determined to have complete control over his next production, which became the groundbreaking Sweet Sweetback's Baadasssss Song (1971), privately funded with his own money, and in part by a $50,000 loan from Bill Cosby.

[15] As his intended follow-up to Sweet Sweetback's Baadasssss Song, Van Peebles made the musical film Don't Play Us Cheap.

[16] The film was an adaptation of an earlier stage musical of the same name which Van Peebles had created for performances at San Francisco State College in November 1970.

[18] In 1977, Van Peebles was one of four credited screenwriters on the film Greased Lightning, about the life of pioneering Black NASCAR driver Wendell Scott.

[22][23] In 1995, he co-starred in the American live-action version of Japanese manga Fist of the North Star, alongside Gary Daniels, Costas Mandylor, Chris Penn, Isako Washio, Malcolm McDowell, Downtown Julie Brown, Dante Basco, Tracey Walter, Clint Howard, Tony Halme, and Big Van Vader.

[25] In 2005, it was announced that Van Peebles would collaborate with Madlib for a proposed double album titled Brer Soul Meets Quasimoto.

As well, he wrote and performed in a stage musical, Unmitigated Truth: Life, a Lavatory, Loves, and Ladies, which featured some of his previous songs as well as some new material.

[40] On November 10, 2012, he released a video for the song "Lilly Done the Zampoughi Every Time I Pulled Her Coattail" to go with the album,[41][42] which was announced on his Facebook page.

[44] In 2017, Methane Momma, a short film directed by Alain Rimbert, featured Van Peebles and his narration of poetic work with accompaniment of music by The Heliocentrics.