She attended Sweet Briar College for two years, then moved to New York City in pursuit of a career as an actress and model, and even tested for the part of Scarlett O'Hara in Gone with the Wind. During World War II, she joined the British Women's Auxiliary Air Force, and then the Office of War Information. She taught at Bard College, the Iowa Writers' Workshop, and University of Virginia.

Settle lived for many years in Canada, in England, and in Turkey.

Settle is most famous for a series of novels called the "Beulah Quintet", {Prisons, O Beulah Land, Know Nothing, The Scapegoat, The Killing Ground) which cover the history of West Virginia, and by extension, the United States. She also wrote several works of non-fiction.

She died of lung cancer in Ivy, Virginia, near Charlottesville.

Novels and Memoirs

• The Love Eaters (1954)
• The Kiss of Kin (1955)
• O Beulah Land (1956)
• Know Nothing (1960)
• Fight Night on a Sweet Saturday (1964)
• All the Brave Promises: The Memories of Aircraft Woman 2nd Class 2146391 (1966)
• The Clam Shell (1970)
• Prisons (1973)
• Blood Tie (1977)
• The Scapegoat (1980)
• The Killing Grounds (1982)
• Charley Bland (1989)
• Turkish Reflections: A Biography of Place (1991)
• Addie: A Memoir (1998)
• I, Roger Williams: A Novel (2002)
• Spanish Recognitions: The Road from the Past (2004)

Non Fiction

• All the Brave Promises
• The Scopes trial
• Water World