In 1529 a Spanish lawyer named Nuño Beltrán de Guzmán led an army of 300 Spaniards and 6,000 indigenous people into Aguascalientes. Over the next decade, hundreds of additional Spanish forces moved into the area, which they called Nueva Galicia. When Spaniards were given grants to begin cattle ranching in the Guachechiles territory, military outposts were established to protect the merchant routes into Mexico City. One of these outposts was called La Villa de Nuestra Señora de la Asunción de Aguascalientes: The Village of Our Lady of the Assumption of Aguascalientes. With the approval of King Felipe II of Spain, the town was founded on October 22, 1575, by Don Gerónimo de Orozco, the President of the Royal Audience and Governor of Nueva Galicia.
The region became a war zone over the next several decades as the indigenous people fought the Mixtón Rebellion of 1540-1541 and the Chichimeca War of 1550-1600 in an effort to force back the Spaniards. By 1582, the population of Aguascalientes was down to one military commander, 16 soldiers and two citizens. Finally, in the 1580s, the Spanish began to negotiate a peaceful settlement with the Indians; as a result, the last Indian attack took place in 1593.
A new wave of Spanish settlers arrived in the late 1590s, bringing Indian and black slaves to develop and work the area. By 1610, Aguascalientes had a population consisting of about 25 Spaniards, 20 black slaves, 10 Indians and roughly 150 mixed-race residents of indigenous descent.
In 1617 Aguascalientes achieved the status of an alcaldía mayor, or territory, when it was separated from Lagos de Moreno (part of the state of Jalisco). The region continued to grow despite setbacks, including a massive epidemic from 1738-1739 that killed 1,018 people, mostly Indians.