Later, Tonkawa, Aranamas, Tamiques, Karankawa, Tawakoni, Lipan Apache, and Comanche lived and hunted in the county.

French explorer René Robert Cavelier, Sieur de La Salle[7][8] is believed to have crossed the county on his way westward from Victoria County; and while La Bahia[9] was a common route, no evidence of any settlements exist before the Anglo homesteaders.

In 1825, empresario Green DeWitt[10] received a grant from the Coahuila y Tejas legislature to settle 400 families.

Dewitt County voted in favor of secession from the Union, and sent several military units[15] to serve.

The notorious Sutton–Taylor feud[20][21] began as a Reconstruction-era county law enforcement issue between the Taylor family and lawman William E. Sutton.

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,[22] which originated at Cardwell's Flat, near the present Cuero.

Dewitt's first rail line, the Gulf, Western Texas and Pacific,[23] extended to San Antonio.

Much like ranchers had cattle drives, Cuero poultry growers drove their turkeys down Main Street to the local packing plant.

[28] Each year, the crowds grew to watch the sight and sound of upwards of 20,000 turkeys going through town.

By the 1970s,[31] the event had become a 3-day typical Texas celebration with parades, live entertainment, food booths, and street dances.