The town of Cuero was established in 1872 in response to the construction of the Gulf, Western Texas & Pacific Railroad line. Cuero is known for its close association with the abandoned town of Indianola, a major Texas seaport during the mid-19th century, destroyed by a succession of hurricanes in the late 19th century. Most of its citizens moved to Cuero, where they established prosperous businesses.
The Cuero Commercial Historic District incorporates most of the historic downtown area and includes many businesses that have been in continuous operation throughout the history of the town. The district includes late 19th- and early 20th-century masonry commercial buildings reflecting the period when Cuero developed into an important commercial and agricultural center.
By 1912, Cuero was known as the turkey capital of the world because of its tradition of parading turkeys, raised on local farms, down Main Street. The turkey trot helped to promote the developing poultry industry of Cuero.