Grand Saline's first settlers were the ancient Caddo and Cherokee Indian tribes, who discovered and made use of a large salt prairie south of the town.

The Native Americans used evaporated salt, from the brine stream that flows over the flats, as a commodity they traded for other needed goods.

In the mid-nineteenth century, the tribes moved southeast, having been forced out of the area by Mirabeau B. Lamar, second president of the Republic of Texas, and by general anti-Indian sentiment.

A settler named John Jordan and other newcomers brought their families and set up a primitive salt works.

During the late 1920s, the discovery of the nearby Van oil field brought companies that provided needed supplies.

Grand Saline was also known for its Lone Star Hotel, which was, for a brief time, the home of Hollywood starlet Louise Fazenda, the wife of Warner Brothers executive Hal Wallis.

Agriculture, farming and ranching have long been a major part of the economic life in Grand Saline.

Poultry, livestock, dairy products, lumber and an ice house all played a role in the formation and history of the town.