Larry Charles performed stand-up comedy during the 1970s until he was hired to write for the short-lived Sketch comedy show Fridays, where he worked with Larry David, who would later give him a job as a Writer on Seinfeld and Director on Curb Your Enthusiasm. This began Charles's career in television writing that included The Arsenio Hall Show and eventually Seinfeld.

In 1995, Charles left the writing staff of Seinfeld to join that of another hugely successful mid-1990s sitcom: Paul Reiser's Mad About You.

In 2000, Charles began his first job as a Director on Curb Your Enthusiasm, Larry David's follow-up series to Seinfeld (which Larry David co-created). Charles directed 18 episodes of the hit HBO show.

Charles's feature debut was Masked and Anonymous (2003) which he directed, and co-wrote with Bob Dylan (under the pseudonyms Rene Fontaine and Sergei Petrov, respectively). The film received a mixed reaction from audiences and critics alike; it did poorly at the box office. Charles maintains it takes many viewings to get true enjoyment from the film: "I want the movie to be like a great Bob Dylan song that is listened to over and over and for people to [go] back and see it again and get a lot more things, or totally different things."

Charles's third film was Religulous — a documentary about Bill Maher's take on the state of contemporary religion — which was released in October 2008.