Nettleton's 30-year Broadway career also included roles in such shows as Darkness at Noon, Cat on a Hot Tin Roof God and Kate Murphy, for which she received the Clarence Derwent Award, and Strangers. In 1973, she replaced Rosemary Harris as Blanche DuBois in an acclaimed production of A Streetcar Named Desire. Nettleton also worked regionally and Off-Broadway; in 2004, she appeared in How to Build a Better Tulip.
Nettleton played Lady Macbeth in a 1968 television film of the Shakespeare play opposite Earle Hyman. She also starred in the film versions of Period of Adjustment, The Man in the Glass Booth and The Best Little Whorehouse in Texas.
She worked steadily on television, received Emmy Award nominations for her work on Fear on Trial, The Golden Girls, In the Heat of the Night, and The Last Bride of Salem. She received Daytime Emmy Awards for The American Woman: Portraits of Courage and Insight, She appeared as Virginia Benson on the popular daytime drama General Hospital and had a recurring role in In the Heat of the Night.
Nettleton was married to writer Jean Shepherd from 1961-1967; that union ended in divorce.