[5] Larrea tridentata is a prominent species in the Mojave, Sonoran, and Chihuahuan Deserts of western North America, and its range includes those and other regions in portions of southeastern California, Arizona, southern Nevada, southwestern Utah, New Mexico, and Texas in the United States, and Chihuahua, Sonora, Coahuila, Nuevo León, Zacatecas, Durango and San Luis Potosì in Mexico.

The species grows as far east as Zapata County, Texas, along the Rio Grande southeast of Laredo near the 99th meridian west.

Eventually, the old crown dies and the new ones become a clonal colony from the previous plant, composed of many separate stems all from the same seed.

[14][15][16] King Clone was identified and its age estimated by Frank Vasek, a professor at the University of California, Riverside.

In parts of its range, it may cover large areas in practically pure stands, though it usually occurs in association with Ambrosia dumosa (burro bush or bur-sage).

[21] Owing to the harshness of the germination environment above mature root systems, young creosote bushes are much more susceptible to drought stress than established plants.

Accumulation of fallen leaves, as well as other detritus caught from the passing wind, creates an ecological community specific to the creosote bush canopy, including beetles, millipedes, pocket mice, and kangaroo rats.

Native Americans in the Southwest held beliefs that it treated many maladies, including sexually transmitted diseases, tuberculosis, chicken pox, dysmenorrhea, and snakebite.

[25] In other uses, the reddish-colored lac that exudes from the plant was used by the Tohono O'odham, after boiling, to make a mending glue on broken pottery.

[27] The United States Food and Drug Administration has issued warnings about the health hazards of ingesting chaparral or using it as an internal medicine, and discourages its use.

[28] In 2005, Health Canada issued a warning to consumers to avoid using the leaves of Larrea species because of the risk of damage to the liver and kidneys.