Gregory County is a county in the U.S. state of South Dakota. As of the 2020 census, the population was 3,994. Its county seat is Burke. The county was created in 1862 and organized in 1898. It was named for the politician J. Shaw Gregory.

U.S. Route 281 (US 281) is a north–south United States Numbered Highway. At 1,875 miles (3,018 km) it is the longest continuous three-digit U.S. Route.