Harden, one of five children, was born in La Jolla, California, the daughter of Beverly, a housewife, and Thaddeus Harold Harden, a Texas native who was an officer in the Navy. Harden's family frequently moved because of her father's job, living in Japan, Germany, Greece, California and Maryland. She graduated from Surrattsville High School in Clinton, Maryland in 1976, the University of Texas at Austin with a BA in theatre, and the graduate theatre program at New York University with a Master of Fine Arts.

Harden debuted on Broadway in Tony Kushner's Angels in America in 1993, for which she received a Tony Award nomination (Best Featured Actress in a Play). For her film work, she won a Best Supporting Actress Academy Award for Pollock (2000), and was nominated in the same category for Mystic River (2003).

Other notable films include The Imagemaker (1986), her first screen role, in which she played a stage manager; the Coen Brothers' Miller's Crossing (1990), a 1930s mobster drama in which she gained her first wide exposure; the Disney sci-fi comedy Flubber (1997), a popular hit in which she co-starred with Robin Williams; the supernatural drama Meet Joe Black (1998); Labor of Love (1998), a Lifetime Television movie in which she starred with David Marshall Grant; and an all-star adventure-drama of aging astronauts, Space Cowboys (2000).

She also guest-starred as an FBI undercover agent (named Dana Lewis) posing as a white-supremacist in "Raw", an episode of the popular crime drama Law & Order: Special Victims Unit for which she was nominated for an Emmy Award for best guest actress in a drama series.

In 2007, Harden appeared in several films, including Sean Penn's critically acclaimed Into the Wild, and the Frank Darabont directed "The Mist", based on the story by Stephen King. Her performance as Mrs. Carmody, the religious zealot, was highly acclaimed as one of the year's most talked-about performances. For her work in that film, she was recently honored with the Saturn Award for Best Supporting Actress of 2007. She has also received two nominations for the Independent Spirit Award.

She recently completed filming on Home, in which her co-stars include her daughter, Eulala Scheel, and the comedy The Lonely Maiden with Christopher Walken and Morgan Freeman