The ancestral Puebloan site of Aztec Ruins National Monument is situated along the river in the present day town of Aztec and for much of its course the river flows through native Ute and Navajo lands.
It was fought in the winter of 1540-41 by the expedition of Francisco Vásquez de Coronado against the twelve or thirteen pueblos of Tiwa Indians as well as other Puebloan tribes along both sides of the Rio Grande, north and south of present-day Bernalillo, New Mexico, in what was called the Tiguex Province.
Ysleta del Sur Pueblo (also Tigua Pueblo) is a Puebloan Native American tribal entity in the Ysleta section of El Paso, Texas, comprising a formerly Southern Tiwa-speaking people who were displaced from New Mexico in 1680 and 1681 during the Pueblo Revolt against the Spaniards.