Hamilton's film credits include roles in 12 Monkeys (1995), Jackie Brown (1997), Beloved (1998), True Crime (1999), The Sum of All Fears (2002), The Soloist (2009), Beastly (2011), Beautiful Boy (2018), and Vice (2018).

Hamilton was born in Los Angeles, California but spent most of her childhood in Stony Brook, New York on the north shore of Long Island.

Her father, Ira Winslow Hamilton, Jr., hailed from Bessemer, Alabama, and her mother, the former Eleanor Albertine "Tina" Blackwell, was from Meridian, Mississippi.

Hamilton's performances in Much Ado About Nothing, Tartuffe, Reckless, Family of Mann, and Two Gentlemen of Verona, earned her a reputation as a serious dramatic actor.

More recently, Hamilton earned critical acclaim,[7] her second Obie, and a Lucille Lortel Award nomination for her role as Suzanne Alexander in Adrienne Kennedy's The Ohio State Murders.

She has worked on several projects with director Rodrigo García, notably his films Ten Tiny Love Stories, Nine Lives, and Mother and Child.

Hamilton played the role of Melissa in Men of a Certain Age, an hour-long comedy-drama television series starring Ray Romano, Andre Braugher, and Scott Bakula that ran from 2009 to 2011.