During the '80s and '90s, James Le Gros starred in multiple independent films. His most notable role in the indie film world is in Gus Van Sant's cult classic Drugstore Cowboy (1989). In 1991, Le Gros starred in Kathryn Bigelow's Point Break, and in 2000 he had a recurring role in the TV series Ally McBeal.
Le Gros had a memorable guest appearance on the TV sitcom Friends, playing Phoebe Buffay's inappropriate date. In 2006, he starred alongside Ron Pearlman in The Last Winter, and in 2016, Le Gros starred opposite an all-star female cast of Michelle Williams, Kristen Stewart and Laura Dern in Certain Women.