After graduation, Harrelson moved to New York City. In 1985, he was cast as the naive but genial Midwestern bartender Woody Boyd on the classic television series Cheers, and won an Emmy for the role. His first film was 1986's Wildcats with Goldie Hawn. Harrelson became friends with Wesley Snipes and starred with him in the box-office hits White Men Can't Jump and Money Train. He appeared in mostly minor roles until he starred in Robert Redford's Indecent Proposal in 1993, a role which helped open doors for Harrelson in the film industry.

In 1994 Harrelson starred in arguably his best known role to date, Mickey Knox in Oliver Stone's Natural Born Killers. During this time he also starred in the Farrelly brothers cult classic Kingpin. In 1996, he starred in the title role of the controversial film The People vs. Larry Flynt, for which he received a nomination for the Academy Award for Best Actor. Following this performance Harrelson went to star in films such as Wag the Dog, EDt