[3] The area now occupied by Hughes County was part of Indian Territory in the 19th Century.

The Creeks settled in the northern part, which fell within the Wewoka District of the Creek Nation, while the Choctaws settled in the southern, which fell within portions of Atoka County and Tobucksy County of the Choctaw Nation.

There were absentee groups of Quapaw living along the Red River and in Creek, Choctaw and Cherokee territory.

The town established there was named Holden, for James Franklin Holder, a railroad official.

Despite the county being home to a significant Native American population and, until recently, a substantial Democratic registration advantage, Hughes County has voted Republican in every presidential election in the 21st century.

Agriculture and cattle raising have long been important to the county economy.

Primary crops have been cotton, wheat, corn, oats, peanuts, and soybeans.

The most important other employers in the county are: Davis Correctional Center (which is operated by Corrections Corporation of America), Tyson Foods, Wes Watkins Technology Center, and Aquafarms, which has since gone out of business.

This allows collaboration between the hospitals to improve services and support for patient transfers to higher levels of care when needed.

Hughes County EMS is an ALS level service licensed by the State of Oklahoma, with Paramedics on every unit.

[3] School districts (all K-12) include:[17] The following sites are in Hughes County are listed on the National Register of Historic Places: