Founded in 1881, Chamberlain was named after Selah Chamberlain, a railroad director of the Chicago, Milwaukee and St. Paul Railway, as it was established by European Americans in relation to the construction of the railroad. The city is called "earth dwelling" in Lakota.  According to the United States Census Bureau, the city has a total area of 7.84 square miles (20.31 km2), of which 6.64 square miles (17.20 km2) is land and 1.20 square miles (3.11 km2) is water.

Chamberlain is in Brule County, South Dakota, United States. It is located on the east bank of the Missouri River, at the dammed section of the Lake Francis Case, close to where it is crossed by Interstate 90.

The population of Chamberlain was 2,473 at the 2020 census.  It is the county seat of Brule County.

Chamberlain is home to the South Dakota Hall of Fame, and the 50-foot tall Dignity statue is nearby.