Santa Cruz de Quiché is a town in Guatemala, in the province of El Quiché, of which it is the departmental capital. The town is located at 15.03° North, 91.15° West at an elevation of 2,021 m (6,631 feet) above sea level. The population was about 2l,000 people as of 2003.

Santa Cruz de Quiché was founded by Pedro de Alvarado, a companion of the conquistador Hernán Cortés, after he burned down the nearby Maya capital city of Gumarcaj (or Utatlán, in the Nahuatl language). The oldest buildings, including a large cathedral and clock tower in the central plaza, were constructed out of the stones of the Gumarcaj ruins by the Dominicans. Some think it likely that it was in Santa Cruz where a group of anonymous Quiché nobles of the Nim Ch'okoj class transcribed the Popol Vuh, the sacred text of the Maya.

In Santa Cruz, the former rulers of Cumarcaj were reduced to the status of peasant. As the living conditions were so pitiful in the city, the town of Santo Tomás Chichicastenango, about 20 miles to the south of Santa Cruz, began to swell with the immigration of displaced Mayas and soon passed up Santa Cruz in both size and importance.