Mayersville is a town on the east bank of the Mississippi River, and the county seat for Issaquena County, Mississippi, United States. It is located in the Mississippi Delta region, known for cotton cultivation in the antebellum era. Once the trading center for the county, the town was superseded when railroads were built into the area. The population of the majority-black town was 547 at the 2010 census, down from 795 at the 2000 census.

Issaquena County is a county located in the U.S. state of Mississippi. As of the 2020 Census, its population was 1,338, making it the least populous county in the United States east of the Mississippi River. Its county seat is Mayersville. With a per-capita income of $18,598, Issaquena County is, by that measure, one of the poorest counties in the United States.