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 $24,489, Issaquena County is, by that measure, the third-poorest county in the United States. Issaquena County is located in the Mississippi Delta region.