Julie Brown began her career performing in nightclubs. She was a contestant on the game show Whew! (as Annie Brown). She started working on television with a guest spot on the sitcom Happy Days. She also appeared in the 1981 cult film Bloody Birthday. After a small role in the Clint East woodcomedy film Any Which Way You Can, comedian Lily Tomlin saw Brown at a comedy club and gave her her first big break, a part in her 1981 film The Incredible Shrinking Woman. Tomlin and Brown eventually became close friends. A string of guest starring appearances in a variety of television shows followed

Brown’s film career began in 1988 with the release of the film Earth Girls Are Easy, written, produced by, and starring Brown,[14] it was based loosely on a song by the same name from her debut EP. The film also starred Jeff Goldblum and Geena Davis. Brown cast then-unknown comedians Jim Carrey and Damon Wayans.

She has continued to make television guest appearances and contributed voices to various cartoons, including Animaniacs (as the voice of Minerva Mink), Aladdin as bratty mermaid Saleen, and as the original voice of Zatanna in the Batman: The Animated Series cartoon. Prior to this, she also guest starred on a Tiny Toon Adventures episode as Julie Bruin, a cartoon bear version of herself, in which she guest-starred in her own segment Just Say Julie Bruin, a reference to her music video show. The Just Say Julie Bruin cartoon also was a music video show and in her segment Elmer Fudd guest-starred as Fuddonna, a parody of Madonna and a reference to Julie Brown herself regularly mocking her.