Cape Girardeau County is located in the southeastern part of the U.S. state of Missouri; its eastern border is formed by the Mississippi River. At the 2020 census, the population was 81,710. The county seat is Jackson, the first city in the US to be named in honor of President Andrew Jackson. Officially organized on October 1, 1812, the county is named after Ensign Sieur Jean Baptiste de Girardot, an official of the French colonial years. The "cape" in the county's name is named after a former promontory rock overlooking the Mississippi River; this feature was demolished during railroad construction. Cape Girardeau County is the hub of the Cape Girardeau–Jackson metropolitan area. Its largest city is Cape Girardeau.

Perry County is a county located in the southeastern portion of the U.S. state of Missouri. As of the 2020 census, the population was 18,956. Its county seat is Perryville. The county was officially organized on November 16, 1820 from Ste. Genevieve County and was named after Oliver Hazard Perry, a naval hero of the War of 1812.