Keener officially broke into films with one line in About Last Night (1986). Although she struggled professionally over the next few years one low-quality project had an unexpected dividend. Keener met her future husband, actor Dermot Mulroney in 1987 while working on Survival Quest (1989), after Mulroney became stuck while attempting to scale a cliff.

She also guest-starred as an artist on an episode of Seinfeld called "The Letter". She played Jerry's girlfriend, an artist who painted the infamous portrait of Kramer. Keener then earned her first starring role in Johnny Suede with the then unknown, Brad Pitt. Her performance gained critical acclaim and earned her her first Independent Spirit Award nomination for Best Female Lead. She went on to work with director Tom Dicillo, again, in Living in Oblivion (1995). Two years later she was once again nominated for an Independent Spirit Award for her performance in Walking and Talking, an independent cult-comedy film. Critics fell