[3] After performing to favorable reviews with Geraldine Page in repertory theatre at the New Lake Zurich Playhouse in 1946 and with the Woodstock Players the following year, her professional acting career began in 1949.

[4] Nettleton performed in many guest-starring roles on television shows, including The Twilight Zone (episode "The Midnight Sun", 1961), Naked City, Route 66, Mr. Novak, The Alfred Hitchcock Hour (episode "The Dark Pool", 1963), The Eleventh Hour, Hawaii Five-O, Dr. Kildare, Twelve O'Clock High, The Fugitive, The F.B.I., Cannon, Bonanza, Gunsmoke, The Virginian and Daniel Boone.

She appeared in the pilot episode of The Eddie Capra Mysteries in 1978 and in hit TV miniseries such as Washington: Behind Closed Doors and Centennial.

[5] In 1987, Nettleton portrayed Penny Vanderhof Sycamore on the TV series version of the Kaufman and Hart comedy play You Can't Take It with You with Harry Morgan and Richard Sanders.

The first was for her role as Susan B. Anthony in the television film The American Woman: Profiles in Courage (1977), and the second for "A Gun for Mandy" (1983), an episode of the religious anthology Insight.

She received an Emmy Award nomination for Outstanding Guest Actress in a Comedy Series for the Golden Girls episode "Isn't It Romantic?".

A lifetime member of the Actors Studio,[6] Nettleton made her Broadway debut in the 1949 production of Dalton Trumbo's play The Biggest Thief in Town.