Gondry was born in Versailles, France. His career as a filmmaker began with creating music videos for the French rock band Oui Oui, where he also served as a drummer. The style of his videos caught the attention of music artist Björk, who asked him to direct the video for her song "Human Behaviour". The collaboration proved long-lasting, with Gondry directing a total of six music videos for Björk. Other artists who have collaborated with Gondry on more than one occasion include Daft Punk, Radiohead, The White Stripes, The Chemical Brothers, The Vines, and Beck. Gondry has also created numerous television commercials. He pioneered the "bullet time" techniques used in The Matrix, notably in his "Like a Rolling Stone" video for the Rolling Stones and a 1998 commercial for Smirnoff vodka, as well as directing a trio of inventive holiday-themed commercials for GAP.

Gondry is often cited, along with directors Spike Jonze, David Fincher, and Marcus Nispel, as representative of the influx of music video directors into feature film. Gondry made his feature film debut in 2001 with Human Nature, garnering mixed reviews. His second film, Eternal Sunshine of the Spotless Mind (also his second collaboration with screenwriter Charlie Kaufman), was released in 2004 and received many rave reviews. Eternal Sunshine utilizes many of the image manipulation techniques that Gondry had experimented with in his music videos. Gondry won an Academy Award alongside Kaufman and Pierre Bismuth for the story of Eternal Sunshine. The style of Gondry's music videos often relies on videography and camera tricks which play with frames of reference.

Gondry also directed the musical documentary Dave Chappelle's Block Party (2006) which followed comedian Dave Chappelle as he attempted to hold a large, free concert in the Bedford-Stuyvesant neighborhood of Brooklyn. His following film, The Science of Sleep, hit theaters in September, 2006. This film stars Mexican actor Gael García Bernal, and marks a return to the fantastical, surreal techniques he employed in Eternal Sunshine.

In September 2006, Gondry made his debut as an installation artist at Deitch Projects in New York's SoHo gallery district. The show, called "The Science of Sleep: An Exhibition of Sculpture and Pathological Creepy Little Gifts" featured props from his film, The Science of Sleep, as well as film clips and a selection of gifts that the artist had given to women he was interested in, many of them former or current collaborators, Karen Baird, Kishu Chand, Dorothy Barrick and Lauri Faggioni. (see ) A leitmotif of the film is a 'Disastrology' calendar, Gondry commissioned the painter Baptiste Ibar to draw harrowing images of natural and human disasters.

His brother Olivier 'Twist' Gondry is also a television commercial and music video director creating videos for bands such as The Stills, The White Stripes, Hot Hot Heat and The Vines (see ).

Gondry was an Artist in Residence at the Massachusetts Institute of Technology in 2005 and 2006. He recently directed the video for Paul McCartney's "Dance Tonight" from the album "Memory Almost Full".