Before the arrival of the Aztecs in the 1400s, several tribes inhabited the Oaxaca region, including the Zapotec and Mixtec. The remnants of their civilizations can be seen at archaeological sites such as Monte Alban and Mitla. Then, around the 1430s, the Aztecs settled the region and gave the Central Valley the name Huaxyácac, or “Place of the guaje trees,” due to its abundance in the area. From this name came the later Spanish Oaxaca, which is now the name for both the city and state.

The first European settlement, which was called Segura de la Frontera, was founded in 1521 by the Spanish explorer Hernán Cortés , and the town was quickly given a royal charter in 1532 by Emperor Charles V under the name of Antequera de Guaxaca. Though Cortés declared that the whole valley belonged to him, as he had explored and settled it according to the common conquistadore practices of the times, but the Spanish kingdom supported the townspeople, and Oaxaca developed from the land allotted to the royal colony. The streets were planned in the traditional Spanish colonial style, with streets laid out in a rectangular grid surrounding a central square. This layout can still be seen today in Oaxaca’s historic city center.