During the Viceroyalty of New Spain it was divided into the district of Nueva Galicia and was composed almost completely of the indigenous people who in turn were peasants.

The region of Tlajomulco belonged to the lordship of Tonallan and the inhabitants were called Tlajomulcas.

Tlajomulco was founded with the authority of Lord De Tonalá, in appreciation to Pitláloc, Copaya, Pilili and Totoch, for resisting the invasion of the Purépecha.

In the first half of the 16th century, Coyotl being a tyrant, suppressed the people of Cuyutlán, Cuescomatitlán, Cajititlán, Atlixtac (Santa Anita) and Xuchitlán, with fees until in 1530 it was conquered by Nuño Beltrán de Guzmán, who upon arriving in Tlajomulco was well received by the tyrant Coyotl, who he helped in the conquest of Tonalá.

Seventeen plastic bags with human remains were found in colonia Chulavista in January 2021.