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Barbour County was established on December 18, 1832, from former Muscogee homelands and a portion of Pike County. Between the years of 1763 and 1783 the area which is now Barbour County was part of the colony of British West Florida. After 1783 the region fell under the jurisdiction of the newly created United States of America. The Muscogee Creek Confederacy was removed to territory west of the Mississippi River. The fertile land was developed by southern migrants as large cotton plantations dependent on slave labor. Due to the number of slaves, the population was soon majority black, a proportion that continued for decades. In the 21st century, the population has a slight white majority, but blacks make up more than 46% of the residents, which results in highly competitive politics.
In 1833, Louisville was chosen as the first county seat for Barbour County. The county seat was moved in 1834, after an eleven-member committee selected Clayton because of its central geographic location. Its boundaries were altered in 1866 and 1868. The Election Riot of 1874 occurred near Comer.
By the 1870s, the city of Eufaula had surpassed Clayton in size, sparking debate about whether the county seat should be moved to the county's commercial center or remain at its geographic center. Reaching a compromise, the legislature passed Act No. 106 on February 12, 1879, to establish county courts in both Eufaula and Clayton. Today, two county courthouses continue to operate in Barbour County.