The name Okmulgee is derived from the Hitchita (Lower Creek) word okimulgi, meaning "boiling waters".

The Creek Nation was removed into this part of Indian Territory along the Trail of Tears after signing treaties exchanging their land in Georgia and Alabama in 1826 and 1832.

The Creek Nation government, led by chief Samuel Checote, revised its constitution in 1867 and designated Okmulgee as its capital in 1868.

[3] Railroads came to the area in 1900, when the St. Louis, Oklahoma and Southern Railway (later the St. Louis and San Francisco Railway or Frisco) built a line from Sapulpa, Oklahoma via Okmulgee to a place near the Red River.

The Shawnee, Oklahoma and Missouri Coal and Railway (later also acquired by the Frisco) built a line from Muskogee to Okmulgee in 1902–03.

[9] The Deep Fork of the North Canadian River is the principal waterway in the county.

Deep Fork National Wildlife Refuge lies within the southern part of the county.

[17] County services, including the District Court, Assessor, County Clerk, Jail, and Sheriff's office, are all located between 6th and 8th St, and Alabama and Seminole Avenues, in the City of Okmulgee.

[18] Despite a wide Democratic registration advantage as recently as the late 2010s, the county—like every Oklahoma county since 2000—has favored the Republican candidate for president in every election since 2000, with the Republican margin of victory increasing with every election.

The following sites in Okmulgee County are listed on the National Register of Historic Places: