The Santa Cruz River is located in southern Arizona, and northern Sonora, Mexico. The Santa Cruz has its headwaters in the high intermontane grasslands of the San Rafael Valley to the southeast of Patagonia between the Canelo Hills to the east and the Patagonia Mountains to the west, just north of the U.S.-Mexican border. It flows southward into Mexico past Santa Cruz, Sonora and turns westward around the south end of the Sierra San Antonio near Miguel Hidalgo (San Lazaro), thence north-northeast to reenter the United States just to the east of Nogales and southwest of Kino Springs. It then continues northward from the International border past the Tumacacori National Historical Park, Tubac, Green Valley, Sahuarita, San Xavier del Bac, and Tucson to the Santa Cruz Flats just to the south of Casa Grande and the Gila River. Between Nogales and Tucson the river valley is flanked by the Patagonia and Santa Rita Mountains on the east and the Tumacacori and Sierrita Mountains on the west. The Santa Cruz River is usually a dry riverbed through much of the year, unless the area receives significant rainfall. This was not always the case, as it was a combination of human errors and natural catastrophes in the late nineteenth century that led to the decline of the Santa Cruz. The city of Nogales, Sonora has been releasing treated sewage into the Santa Cruz River. This has resulted in the revival of several miles of riverbank within and north of the city of Nogales, Arizona.
As of 2017 there's been an improvement in the fish habitat in the 23-mile stretch of the Santa Cruz River ever since Pima County’s wastewater treatment facilities, the Tres Rios Water Reclamation Facility and the Agua Nueva, were upgraded in 2013. The Sonoran Institute, joined by Pima County, has been working with the Arizona Game and Fish Department, the University of Arizona, the U.S. Geological Survey and the U. S. Fish and Wildlife Service to conduct an annual fish survey.