The reservoir occupies a series of meanders between the two rivers; its outflow passes through Amistad Dam on the lake's southern side, from which the Rio Grande continues southeastward toward the Gulf of Mexico.

[1] The Amistad gambusia, a fish species endemic to the area, was eliminated in the wild when the filling of the reservoir in 1969 submerged Goodenough Spring, its only known habitat, under about 70 feet (21 m) of water.

After the Mexican–American War, American pioneers such as John Coffee Hays travelled through the area in developing a reliable road from San Antonio to El Paso.

[3] A 1944 treaty between the United States and Mexico proposed the construction of a major dam and reservoir on the Rio Grande to provide flood control, water conservation, irrigation, hydroelectric power, and recreation to the area.

[4] Amistad Dam's construction began in December 1964 and was completed in November 1969, after which the reservoir was filled, flooding a series of valleys around the confluence of the Rio Grande and the Devils River.