Agnes Moorehead was born on December 6, 1900, in Clinton, Massachusetts, to John Henderson Moorehead, a Presbyterian minister, and Mary Mildred McCauley. Moorehead grew up in Reedsburg, Wisconsin, where her father had a pastorate. She said she learned to act by mimicking members of her father's congregation.
Years later, she would spend hours at the docks in New York City, listening to immigrants and studying their voices and mannerisms. She made her first public performance - at the age of three - singing "The Lord Is My Shepherd" at a church program arranged by her father.
At age ten she was in summer stock. At twelve she was in a ballet chorus at the St. Louis Municipal Opera, and at sixteen, she sang on a new St. Louis radio station.