Archaeological excavations in the Frio Canyon region revealed Paleo-American, Archaic, and Neo-American occupations.

Later, several Native American tribes, including Lipan Apache, Comanche, and Tonkawa inhabited or traversed the area.

[7] Anglo-American settlement of the area began in 1856 when John Leakey, his wife Nancy, and a few others settled near a spring along the banks of the Frio River.

In its first few years, the community was a lonely outpost that was subject to frequent Indian raids, which continued until 1882.

[9] During the early 1900s, ranching superseded lumber, cotton cultivation, and corn production in importance to the local economy.

[11] In 1919, Real County Judge Ed Kelly established the Leakey Independent School District.

On March 29, 2017, thirteen senior citizens from the First Baptist Church of New Braunfels in Comal County who had completed a retreat at Alto Frio were killed when Jack D. Young, the 20-year-old driver of a pickup, crashed into the church minivan on U.S. Highway 83 inside Uvalde County near the state park.

Jody Kuchler, a welder from Leakey who saw the accident, said that the driver of the church vehicle moved over to try to avoid Young's incoming pickup but was blocked by the guard rail.

[12] According to the United States Census Bureau, the city has a total area of 0.6 square miles (1.6 km2), all land.

[15] The climate in this area is characterized by hot, humid summers and generally mild to cool winters.

As of the 1970s, much of Leakey's income derived from deer hunters traveling there in the fall and from tourists in the summer.