Santa Cruz del Quiché was founded by Pedro de Alvarado, a companion and second in-command of conquistador Hernán Cortés, after he burned down the nearby Maya capital city of Q'umarkaj (or Utatlán, in the Nahuatl language).

Some think it likely that it was in Santa Cruz where a group of anonymous K'iche' nobles of the Nim Ch'okoj class transcribed the Popol Vuh, the sacred text of the Maya.

It was important for Las Casas that this method be tested without meddling from secular colonists, so he chose a territory in the heart of Guatemala where there were no previous colonies and where the natives were considered fierce and war-like.

Because it had not been possible to conquer the land by military means, the governor of Guatemala, Alonso de Maldonado, agreed to sign a contract promising that if the venture was successful he would not establish any new encomiendas in the area.

Shielded by their apostolic privileges granted to convert natives into Catholicism, the missionaries only responded to their order local authorities, and never to that of the Spanish government or the secular bishops.

The doctrines were founded at the friars discretion, given that they were completely at liberty to settle communities provided the main purpose was to eventually transfer it as a secular parish which would be tithing of the bishop.

[9] In the 20th century, the Pan-American Highway passed Santa Cruz by, making it less a gateway to the Western Highlands and only the main stop on the road to the North of el Quiché.

[citation needed] During the Guatemalan Civil War Santa Cruz del Quiché found itself in the area where the Ejército Guerrillero de los Pobres - one of the guerrilla organizations that operated in Guatemala - was active.

This organization justified its terrorist attacks against private and public infrastructure by saying that they only impacted the economic interests of both the state and the country's productive sector, and that it made the Guatemalan Army more vulnerable.

The maya k'iche' population that looked for refuge in the mountains was labeled as "guerrilla" by the Army, which tighten military controls around them and continuous attacks that made it extremely hard to get food or medical attention.