St. Clair was born in Hutchinson, Kansas. Her father, US Representative George A. Neeley, died when Margaret was seven, but left her mother well provided for. With no siblings, Margaret recalled her childhood as "rather a lonely and bookish one." When she was seventeen, she and her mother moved to California. In 1932, after graduating from the University of California, Berkeley, she married writer Eric St. Clair. In 1934 she earned a Master of Arts in Greek Classics. The St. Clairs lived in a hilltop house with a panoramic view in what is now El Sobrante, California, where Margaret gardened; she also bred and sold dachshund puppies.