The area now covered by Okfuskee County was occupied by the Quapaw and Osage tribes until 1825, when they ceded the land to the United States government.

During the Civil War, Thlopthlocco served as headquarters for Confederate Col. Douglas H. Cooper.

Okfuskee, a Creek town, grew up around Samuel Checote's trading post after the Civil War.

Of 3,142 counties in the United States in 2014, the Institute for Health Metrics and Evaluation ranked Okfuskee County 2,986 in the life expectancy at birth of male residents and 3,091 in the life expectancy of female residents.

Okfuskee was one of only a few counties in the United States to suffer a decline in life expectancy for women between 1980 and 2014.

[12] In 2020, the Robert Wood Johnson Foundation ranked Okfuskee country as number 73 of 77 counties in Oklahoma in "health outcomes," as measured by length and quality of life.

[13] The following sites in Okfuskee County are listed on the National Register of Historic Places: Okfuskee was the home county of American folk icon Woody Guthrie, who was born in Okemah.

Guthrie refers to Okfuskee in one of his lost lyrics, "Way Over Yonder In the Minor Key."

The lyrics were set to music by Billy Bragg and Wilco for their 1998 collaboration, Mermaid Avenue.