Tequixquiac remained in the Tepaneca district of the Aztec Empire under the authority of the lord of Tacuba, paying tribute to him at Hueypoxtla.

The inhabitants of pre-Conquest Tequixquiac were known for their strict honor code and being advanced in medicine, education, architecture, and civil engineering.

[2] After the fall of the Aztec empire to the Spanish, Hernán Cortés awarded the town and the area around it as an encomiendas to two conquistadors: Martín López, who constructed the brigantines that helped destroy Tenochtitlan and Andrés Núñez.

Indian families were displaced off their lands in 1552 by Francisco López de Tlaltzintlale to make way for more Spanish settlers and new Christians from Spain and Portugal (Crypto-Jews).

A railway to connect Mexico City with the rest of the country was built through here in 1917 on what is now Alfredo del Mazo street, but was dismantled for political reason in 1945.

Santiago Tequixquiac hasn't united with other towns, has got many farms and growing land between other urban areas, but has arrived here more people come from others places.

Other small river is Río Salado de Hueypoxtla this same cross the urban place, is using for irrigation growing lands.

Since 1999, the city has been divided into 2 administrative Agricultural colonies (colonias ejidales in Spanish),[6] is urban sectors consolidated in the 20th century on communal land by farmer's son homes : The Agricultural colonies (colonias ejidales) are based mostly on communal land divisions over neighborhood pad or way, and several are former urban sectors annexed by the town seat of Santiago Tequixquiac since 1960.

The first European people who established this town were Hernán Cortés's soldiers from Spain and Portugal, man who given the encomiendas in Coyoacán, some were Marranos or New Christians (Sephardic settlement converted to Roman Catholic religion).