The area had been inhabited for thousands of years by indigenous peoples of varying cultures. Historic American Indian tribes at the time of European-American settlement were the Pensacola and Muscogee, known among the English as the Creek.
Escambia County had been part of Spanish colonial settlement before the United States acquired it in 1818. The county was organized by European-Americans on July 21, 1821; it was named for the Escambia River. The name "Escambia" may have been derived from the Creek name Shambia, meaning "clear water", or the Choctaw word for "cane-brake" or "reed-brake". The Choctaw were another major tribe in the Southeast.
Created on the same date, Escambia and St. Johns Counties were Florida's two original counties, covering the entire territory within modern state boundaries. The Suwannee River was the border between them, following a winding path from the northern border of the state to the Gulf of Mexico. Essentially, the Escambia county government had jurisdiction over the "panhandle" and "big bend" areas, and St. Johns over the remainder of the entire state.
As population increased in the frontier territory, 21 counties were later organized from Escambia county directly or indirectly. They include Jackson (1821), Gadsden (created from Jackson)(1823), Leon (1824), Walton (1824), Washington (created from Jackson and Walton)(1825), Hamilton (1827), Jefferson (1827), Madison (created from Jefferson) (1827), Franklin (1832), Calhoun (1838), Santa Rosa (1842), Wakulla (created from Leon) (1843), Holmes (created from Jackson and Walton) (1848), Liberty (created from Gadsden) (1855), Lafayette and Taylor (created from Madison) (1856), Bay (created from Washington) (1913), Okaloosa (created from Santa Rosa and Walton) (1915), Dixie (created from Lafayette) (1921), and Gulf (created from Calhoun) (1925). The number of counties in Florida since 1925 has been stable at 67.