The blues-rock group Indigenous is originally from this community, as is early 20th-century author and activist Zitkala-Sa. The largest community on the reservation is the city of Wagner, which is the location of the tribal headquarters. After the Osage Indian Reservation, it is the second-largest Indian reservation that is located entirely within one county. The population as of the 2010 census was 6,465 inhabitants.

It has a land area of 665.712 sq mi (1,724.186 km²) and a total area (land and water) of 684.406 sq mi (1,772.604 km²), and a resident population of 6,500 persons as of the 2000 census. The reservation occupies the easternmost 60 percent of Charles Mix County in southeastern South Dakota, United States and abuts the Missouri River along its southwest border. The Yankton Indian Reservation is the homeland of the Yankton Sioux Tribe of the Dakota tribe.