Until the Spanish conquest, the northern central highlands were inhabited by fierce seminomadic tribes known to the Aztecs as Chichimecs. They resisted Spanish expansion longer than other Mexican peoples, but were ultimately conquered in the late 16th century. The wealth subsequently amassed by the Spanish was at the cost of many Chichimecs, who were used as slave labor in the mines.

This historically volatile region sparked the criollo fight for independence from Spain, which was plotted in Querétaro and San Miguel de Allende and launched from Dolores Hidalgo in 1810. A century later Francisco Madero released his revolutionary Plan de San Luis Potosí and the 1917 signing of Mexico's constitution in Querétaro cemented the region's leading role in Mexican political affairs.

In more recent times the region has flourished economically, due in part to the boom in the motor, aerospace, manufacturing and agricultural industries, particularly around Querétaro, while San Miguel attracts many weekenders from Mexico City and a constant stream of well-heeled creatives from the USA.