In 2010, the center of population of South Dakota was located in eastern Buffalo County.

According to the 2013 Small Area Income and Poverty Estimates of the U.S. Census Bureau, about 41% of county residents live in poverty, making it the fifth-poorest county in South Dakota.

Median household income in 2013 was $21,572, making it the lowest-earning county in South Dakota and the United States.

[7] The Missouri River flows southerly along the county's western boundary.

The county terrain consists of semi-arid rolling hills, generally sloping to the south and east.

[8] As first organized, the county occupied an extensive area, bounded on the north by Canada, southwest and west by the Missouri River, having Montana for a part of its northwest boundary, and comprising a large portion of the "Plateau du Coteau du Missouri", and a part of the Miniwakan or Devil's Lake.

However, many people in Buffalo County are also socially conservative, with this county being the only one in the state to both vote for Kamala Harris for president and vote against 2024 South Dakota Amendment G, which would have established a right to abortion in South Dakota's constitution.