The Alta has seen the most study by archaeologists, with evidence for human settlement going back to the Archaic and Early Formative periods.

Long considered to be part of the larger Mixteca region, groups living in the Baja were probably more culturally related to neighboring peoples in Eastern Guerrero than they were to the Mixtecs of the Alta.

Originally from Tilantongo in the Alta, Eight Deer and his armies conquered several major and minor kingdoms on their way to the coast, establishing the capital of Tututepec in the Lower Río Verde valley.

According to West, "the Mixtec of Oaxaca...were the foremost goldsmiths of Mesoamerica," which included the "lost-wax casting of gold and its alloys.

[10] In the 1450s, Mixtecs would be weakened after the Aztec armies crossed the mountains into the Valley of Oaxaca with the intention of extending their hegemony.

In recent years a large exodus of indigenous peoples from Oaxaca, such as the Zapotec and Triqui, has seen them emerge as one of the most numerous groups of Amerindians in the United States.

There is considerable documentation in the Mixtec (Ñudzahui) native language for the colonial era, which has been studied as part of the New Philology.

In the second half of the colonial period, there were bilingual Mixtec merchants, dealing in both Spanish and indigenous goods, who operated regionally.

However, in the Mixteca “by the eighteenth century, commerce was dominated by Spaniards in all but the most local venues of exchange, involving the sale of agricultural commodities and indigenous crafts or the resale of imported goods.”.

[14] Despite the development of a local exchange economy, many Spaniards with economic interests in Oaxaca, including “[s]ome of the Mixteca priests, merchants, and landowners maintained permanent residence in Puebla, and labor for the obrajes (textile workshops) of the city of Puebla in the sixteenth and seventeenth centuries was sometimes recruited from peasant villages in the Mixteca.

"[15] There is evidence of community litigation against Mixtec caciques who leased land to Spaniards and the growth of individually contracted wage labor.

The valley of Oaxaca itself was often a disputed border region, sometimes dominated by the Mixtec and sometimes by their neighbors to the east, the Zapotec.

An ancient Coixtlahuaca Basin cave site known as the Colossal Natural Bridge is an important sacred place for the Mixtec.

The Mixtec are well known in the anthropological world for their Codices or phonetic pictures[clarification needed] in which they wrote their history and genealogies in deerskin in the "fold-book" form.