The Mayersville Archeological Site, added to the National Register of Historic Places in 1980, is on privately owned land.

It contains the remains of earthwork mounds constructed primarily in the Mayersville phase ( AD 1200–1400) of the earlier Mississippian culture.

A 1950 survey by Philip Phillips of the Peabody Museum of Archaeology and Ethnology reported eleven ancient mounds.

By the time the site was nominated by the state to the National Register of Historic Places, two mounds had been completely destroyed, a third one was nearly gone, three were reduced in size by plowing, and five remained nearly as described.

It attracted shifting populations of river crews, gamblers, and traders, as well as show boats during low water times.

[6][7][8][9] In January 1885, black saloon keeper Ebenzer Fowler was rumored to have sent an insulting letter to a white woman in the town.

The county sheriff called in 22 members of Vicksburg's militia, the "Volunteer Southrons", for assistance.

The construction of a levee following the hugely destructive flood of 1927 cut off direct river access for the town, causing further decline.

Mayersville's small population and quiet character are in sharp contrast to its years as a booming Mississippi River port.

Mayersville is in northern Issaquena County, just east of the Mississippi River, from which it is separated by a levee.

According to the United States Census Bureau, the town of Mayersville has a total area of 1.1 square miles (2.9 km2), all land.