In 1650, Jose Romo de Vivar became the first European who is thought to have visited the area of Nogales. Early in the eighteenth Francisco Eusebio Kino, an Italian missionary, established several missions around Nogales, notably at Tumacacori, Huevavi, and Cibuta.

The city of Nogales was officially founded in 1882 along a north-south rail line to promote trade between the United States and Mexico, and in 1920 it received its name and was the first city in Sonora to initiate manufacturing industry. Nowadays, it is still the main industrial manufacturing and exportation city in the state and has the main customs and immigration services in Sonora.