Nascuda Susan Abigail Tomalin, es formà com a actriu al Catholic University of America Drama School de Nova York (1964-1968). Debutà a Joe (1970), de John G. Avildsen, i posteriorment ha actuat en un gran nombre de pel·lícules, com a protagonista o coprotagonista: The Front Page (1974, Billy Wider), The Rocky Horror Picture Show (1975, Jim Sharman), Dragonfly (1976, Gilbert Cates), The Other Side of Midnight (1977, Charles Jarrott), Pretty Baby (1978, Louis Malle), King of the Gipsies (1978, Frank Pierson), Atlantic City (1980, L. Malle), Tempest (1982, Paul Mazursky), The Hunger (1983, Tony Scott), The Buddy System (1984, Glenn Jordan), Compromising Positions (1985, Frank Perry), The Witches of Eastwick (1987, George Miller), Bull Durham (1988, Ron Sheldon), The January Man (1989, Pat O’Connor), White Palace (!990, Luis Mandoki), Thelma and Louise (1991, Ridley Scott), Lorenzo’s Oil (1992, George Miller), The Client (1994, Joel Schumacher), Safe Passage (1994, Robert Allan Ackerman), Dead Man Walking, (1995), dirigida per Tim Robbins, de qui fou parella en 1988-2009, i que li valgué l’Oscar a la millor actriu principal), Twilight (1998, Robert Benton), Stepmom (1998, Chris Columbus), Anywhere but Here (1999, Wayne Wang), Time of our Lives, (2000), Moonlight Mile, (2002, Brad Silberling), The Banger Sisters (2002, Bob Dolman), Noel (2004, Chazz Palminteri), Shall We Dance? (2004, Peter Chelsom), Alfie (2004, Charles Shyer), Romance and Cigarretes (2005, John Turturro), Bernard and Doris (2006, Bob Balaban), Enchanted (2007, Ann Turner), Mr Woodcock (2007, Craig Gillespie), Speed Racer (2007, de les germanes Wachowski), Emotional Arithmetics (2007, Paolo Barzman), The Lonely Bones (2009, Peter Jackson), The Greatest (2009, Shana Feste), The Meddler (2015, Lorene Scafaria).
A més, ha actuat en diverses sèries (Mussolini and I, 1985; Anno Domini, 1985; The Secret Life of Marilyn Monroe, 2015; Feud, 2017) i telefilms (Earthly Possessions, 1999, de James Lapine; The Exonerated, 2005, de Bob Balaban, You don’t Know Jack, 2010, de Barry Levinson, i The Miraculous Year, 2011, de Kathryn Bigelow). Coneguda també pel seu activisme en causes humanitàries, ha rebut nombrosos guardons, entre els quals destaca el premi d’Honor del Festival Internacional de Cinema de Catalunya (2017).