The museum is located in the house that served as John Nance Garner's home for more than thirty years and tells the stories of the remarkable lives of John Nance "Cactus Jack" Garner and Dolph Briscoe, both Uvalde natives and historically important political figures from Texas. The John Nance Garner House was designated as a National Historic Landmark in 1976.

Garner represented Uvalde in Congress for 30 years before becoming the nation’s vice president under Franklin D. Roosevelt. He transformed the vice presidency into a powerful executive office and was responsible for shepherding through much of Roosevelt’s early New Deal legislation.

Briscoe served as Texas governor from 1973 to 1979. He led a distinguished career in public service, business, and ranching. During his six years as governor, Briscoe presided during a period of reform in state government as Texas's population and commerce boomed. Following his two terms as governor, Briscoe returned to the cattle ranching and banking business in Uvalde.

The Briscoe-Garner Museum is one of five divisions of the Dolph Briscoe Center for American History, an organized research unit of The University of Texas at Austin.