Kellerman's acting career spanned over 60 years. Her role as Major Margaret "Hot Lips" Houlihan in Robert Altman's film M*A*S*H (1970) earned her an Oscar nomination for Best Actress in a Supporting Role. After M*A*S*H, she appeared in a number of the director's projects: the films Brewster McCloud (1970), Welcome to L.A. (1976) (produced by Altman, directed by his protegé, Alan Rudolph), The Player (1992) and Prêt-à-Porter (1994), and the short-lived anthology TV series Gun (1997). In addition to her work with Altman, Kellerman appeared in films such as Last of the Red Hot Lovers (1972), Back to School (1986), plus many television series such as The Twilight Zone (1963), The Outer Limits (1965), Star Trek (1966), Bonanza (1966, 1970) The Minor Accomplishments of Jackie Woodman (2006), 90210 (2008), Chemistry (2011), and Maron (2013).

Besides her extensive roster of film and television roles, Kellerman also delved into music, releasing an album in the 1970s and performing live, including at New York’s Metropolitan room in 2010. Kellerman also contributed songs to the soundtracks for Brewster McCloud (1970), Lost Horizon (1973), Rafferty and the Gold Dust Twins (1975), and Boris and Natasha: The Movie (1992). In addition, Kellerman did commercial voiceover work for Hidden Valley Ranch salad dressing, Mercedes-Benz and Revlon. Kellerman's animation work includes The Mouse and His Child (1977), Sesame Street Presents: Follow That Bird (1985), Happily Ever After (1990), Dinosaurs (1992), Unsupervised (2012), and The High Fructose Adventures of Annoying Orange (2013). In April 2013, she released her memoir Read My Lips: Stories of a Hollywood Life, describing her trials and tribulations in the entertainment business. She died at age 84 due to complications from dementia on February 24, 2022".