The city is home to the National Seashore's visitor center and boat access; the St. Marys Submarine Museum, and Crooked River State Park.

Settlement for colonial Georgians became legal after the Treaty of Paris in 1763, when Britain exchanged some territory with Spain after defeating France in the Seven Years War.

Following independence in the American Revolutionary War, local inhabitants of Camden County gathered on Cumberland Island and signed a charter for "a town on the St. Marys" on November 20, 1787.

These twenty city founders are named on an historical marker in downtown St. Marys: Isaac Wheeler, William Norris, Nathaniel Ashley, William Ashley, Lodowick Ashley, James Seagrove, James Finley, John Fleming, Robert Seagrove, Henry Osborne, Thomas Norris, Jacob Weed, John Alexander, Langley Bryant, Jonathan Bartlett, Stephen Conyers, William Ready, Prentis Gallup, Simeon Dillingham and Richard Cole.

[6] Accounts differ regarding the origin of the name—some say it is named after the St. Marys River, while others say it comes from a seventeenth-century Spanish mission, Santa Maria, on nearby Amelia Island, Florida.

On June 29, 1796, the Treaty of Colerain was signed just up the river from St Marys between the United States and the Creek Nation, the indigenous inhabitants of this territory.

St. Marys town founder Langley Bryant served as the official interpreter between the Creek Indians and the United States.

St. Marys has a humid subtropical climate (Cfa) with long, hot summers and short, mild winters.As of the 2020 United States census, there were 18,256 people, 6,966 households, and 4,998 families residing in the city.