St. Marys is the county seat of Pleasants County. Frenchmen Isaac and Jacob LaRue, now buried on nearby Middle Island, settled here in 1790 on land granted to them for service in the Revolutionary War. The town was established in 1849 by Alexander H. Creel. According to legend, Creel had a vision of the Virgin Mary while passing the site in a boat. She directed him to look at the (West) Virginia shore, saying that a happy and prosperous city would be built there.

Nonetheless, the town saw little growth for its first several years. Then the regional oil boom beginning in the 1860s led to the opening of several cooper shops to make wooden barrels to transport the oil. St. Marys became a shipping port on the Ohio River, as freight was carried down the Ellenboro Pike (State Route 16) to the wharf. From 1910 until 1928, a factory making buttons from river mussel shells employed between 50 and 100 men. In 1914, the Ohio Valley Refining Company began operating and was a major employer until it closed in 1987. Two glass factories operated in St. Marys. Paramount Glass was located near the button factory, and in 1919 St. Marys Glass opened near the refinery. In 1936, the Alley Agate Manufacturing Company began making glass marbles and dishes in the former St. Marys Glass building. Sadly, both glass factories were destroyed by fire.

St. Marys is located on the Ohio River at the intersection of State Routes 2 and 16, east of Parkersburg. The town population peaked at 2,443 in 1960, declining to 1,847 in 2020.