St. Mary's was orginally inhabited the native Americans (Timucuans, Guale, Creeks, and Yamicraw). In 1566, the Spanish occupied the area until the British came in 1686. The Spanish were likely in retreat.
In 1787 a group of 20 men purchased lots in a place called Buttermilk Bluff. Each man invested $38 into a pool to purchase the land for $760. This land became known as St. Mary's, and in 1802 St. Mary's was finally incorporated.
Later the Civil War and the Great Depression damaged the city's economy. It wasn't until the 1940's, when Gilman Paper Co. settled in St. Mary's, and stimulated it's economic recovery.