The Cherokee, Delaware, Shawnee, and Kickapoo Native American peoples began settling in the area around 1820.

[7][8] On December 16, 1837, the Texas Senate declared the treaty null and void,[9] and encroachment upon Cherokee lands continued.

On October 5, 1838, Indians massacred members of the Isaac Killough family[10][11] at their farm northwest of the site of present Jacksonville, leading to the Cherokee War of 1839 and the expulsion of some to Oklahoma.

Domingo Terán de los Ríos[12] and Father Damián Massanet[13] explored the area on behalf of Spain in 1691.

Nuestro Padre San Francisco de los Tejas[15] was originally established in 1690, but was re-established in 1716 by Captain Domingo Ramon.

In 1826, empresario David G. Burnet received a grant from the Coahuila y Tejas legislature to settle 300 families.

Cherokee County voted in favor of secession from the Union, during the build-up to the American Civil War.

In 1872, the International – Great Northern Railroad[18] caused Jacksonville[19] to relocate two miles east, to be near the tracks.

The increase among its Hispanic and Asian American populations represented the nationwide demographic shift since the 2020 census.

School districts within Cherokee County Texas include the following: Areas in Bullard, Jacksonville, New Summerfield, Rusk, and Troup are assigned to Tyler Junior College.