In 1997, he assisted Jean-Pierre Jeunet on the set of Alien Resurrection. On returning to France, he worked with Luc Besson on the production of commercials for Club Internet and L’Oréal as well as on the film Joan of Arc. He also collaborated, as the second assistant director, with Alain Chabat on the production of Astérix & Obélix: Mission Cléopâtre (2002).

Later in 2002, Louis Leterrier directed The Transporter, an action movie starring Jason Statham. Although the US release lists him as artistic director and Corey Yuen as director, the opening credits of the European release grant him directorial credit and list Yuen as action director. Leterrier later entered the so-called “Besson stable” – a group of directors working on films produced by or associated with Luc Besson – alongside Chris Nahon and Pierre Morel. He directed Jet Li in Unleashed, his solo debut feature, a full-length martial arts film (2004). Luc Besson then entrusted him with directorial control of Transporter 2, set this time in Miami.

In 2008, as part of a wave of French directors employed in Hollywood, he directed his first big-budget American film, The Incredible Hulk. His next project, a remake of the 1981 Clash of the Titans produced by Warner Bros., was released on April 2, 2010. Leterrier had mentioned that he would like to create a Clash of the Titans franchise, should the latest film prove to be successful. However, in June 2010, Jonathan Liebesman was named as director of the sequel, leaving Leterrier’s involvement in future films in doubt.

Leterrier directed the spy comedy film Grimsby (2016), written by, and starring, Sacha Baron Cohen. In March 2015, Deadline Hollywood reported that Leterrier was in talks to direct the shark thriller film In the Deep, for Sony Pictures Entertainment. However, on June 3, 2015, TheWrap reported that Leterrier had exited the film due to creative differences and the reduction of the previously told budget.

In 2019, Leterrier directed the first season of The Dark Crystal: Age of Resistance for Netflix, a prequel series to The Dark Crystal consisting of ten hour-long episodes, consisting entirely of puppetry and special effects.