St. Mary's is the county seat of Pleasants County. Its economy is closely related to oil, gas, and glass manufacturing.

The first settlers in 1790 were Isaac and Jacob La Rue. They received the land for their service in the Revolutionary War.

But the community owes its name to Alexander Creel. In the early 1830s, he passed the area on a steamboat, and is supposed to have had a vision of the Virgin Mary. She is said to have told him, "There you behold the site of what will some day be a happy and prosperous city." So in 1843 Creel bought the land. Then later he seemed to have doubts about his vision, sold the land, and moved to Vaucluse. Still later he heard the state was looking for a place to establish the county seat. He knew Vaucluse wouldn't be chosen, but that the site in his vision had a very good chance. So he bought the land back.

The area, then known as Pickens Bottom, was platted by Creel and named St. Mary.