Hannigan's first major film role was in My Stepmother Is an Alien, a science fiction comedy released in 1988; one of her co-stars in the film was actor Seth Green, who would later join her in the regular cast of Buffy as her on-screen boyfriend. Then in 1989, her first regular role on a TV series came when she was cast in the short-lived ABC sitcom Free Spirit. Throughout most of the early-1990s, she appeared in commercials and supporting roles on television shows, including That '70s Show, Picket Fences, Roseanne and Touched by an Angel.

In 1997, Hannigan was cast to play Willow Rosenberg, Buffy's best friend, on the television series Buffy the Vampire Slayer (replacing Riff Regan, who played Willow in the unaired 25-minute pilot). The show became a success, and Hannigan gained recognition, subsequently appearing in several notable films aimed at teenage audiences, including American Pie, American Pie 2, Boys and Girls, and American Wedding. By the time Buffy had ended in 200