Newton made her film debut in Flirting (1991). This Australian movie was also a launch pad for a young Nicole Kidman, with whom she has remained friends. She gained international recognition opposite Nick Nolte in the Merchant-Ivory production of Jefferson in Paris as Sally Hemmings, which led to her being cast in Jonathan Demme's Beloved (1998), in which she played the title character and costarred with Danny Glover, Kimberly Elise, and Oprah Winfrey. She played the female lead Nyah Hall in the film Mission: Impossible II. When this film went over schedule, she had to pull out of the film Charlie's Angels, and her character ultimately went to Lucy Liu.

Between 2003 and 2005, Newton played Makemba "Kem" Likasu, the love interest, and later wife of Dr. John Carter on the American television series ER, and in 2004 also appeared in The Chronicles of Riddick and Crash. In the latter, she played a wealthy black woman who, along with her husband, finds herself the target of a racist