Charles Mix County is a county in the U.S. state of South Dakota. As of the 2020 census, the population was 9,373. Its county seat is Lake Andes. The county was created in 1862 and organized in 1879. It was named for Charles Eli Mix, an official of the Bureau of Indian Affairs influential in signing a peace treaty with the local Lakota Indian tribes. The easternmost approximately 60% of the county comprises the Yankton Indian Reservation.

The Yankton Indian Reservation is the homeland of the Yankton Sioux Tribe of the Dakota tribe.