In 1825, empresario Green DeWitt[8] received a grant from the Coahuila y Tejas legislature to settle 400 families.[9][10] Between 1826 and 1831[11] settlers arrived from Tennessee, Kentucky, Missouri, and other Southern states.
A temporary county government was set up in 1846, with the county seat being Daniel Boone Friar's store at the junction of the La BahÃa Road and the Gonzales-Victoria road.[12] On November 28, 1850, Clinton became the county seat until Cuero became county seat in 1876.
Dewitt County voted in favor of secession from the Union, and sent several military units[13] to serve. During Reconstruction, the county was occupied by the Fourth Corps, based at Victoria.
The notorious Sutton-Taylor Feud[18][19] began as a Reconstruction era county law enforcement issue between the Taylor family and lawman William E. Sutton. It eventually involved both the Taylor and Sutton families, the Texas State Police, the Texas Rangers and John Wesley Hardin. The feud, which lasted a decade and cost 35 lives, has been called the longest and bloodiest in Texas history.
April 1, 1866 marked the first cattle drive on the Chisholm Trail,[20] which originated at Cardwell's Flat, near the present Cuero. The coming of the railroads eliminated the need for the Chisholm Trail. A musuem honoring the pioneer traildrivers is presently under construction.