[4][1] It is named for René-Robert Cavelier, Sieur de La Salle, a 17th-century French explorer.

[1] The area of present-day La Salle County was occupied by the Coahuiltecan Indians until the 18th century, when they were squeezed out by the Spanish from the south and the Apache from the north.

The Treaty of Guadalupe Hidalgo assigned the Nueces Strip to Texas in 1848, but outlaws and hostile Indians delayed settlement of the area.

[1] In 1856, William A. Waugh of Ohio established a ranch where the San Antonio–Laredo road crossed Cibolo Creek.

His ranch headquarters became a stopping point for travelers, and in 1879, a post office was established there with the name Waugh's Rancho.

Iuka, an early settlement located 8 miles west of present-day Cotulla, was established in 1868 by several families and served as a stage stop and marketplace for cattle buyers.

Polish immigrant Joseph Cotulla arrived in La Salle County in 1868 and eventually established a large ranching operation.

La Salle was granted a post office in 1881, and in 1882, was designated the temporary county seat.

The Dilley Independent School District serves a small portion of northwestern La Salle County.

[15] O. Henry, the famous short-story writer, lived and worked on a sheep ranch in La Salle County from 1882 to 1884 before settling in Austin as a pharmacist and bank teller.

[16] For most of its history, La Salle County was a solid Democratic stronghold like most of South Texas.

This political realignment is consistent with shifting trends among Hispanic voters in South Texas.