The earliest human remains in Mexico are chips of stone tools found near campfire remains in the Valley of Mexico and radiocarbon-dated to ca. 21,000 BCE.

Around 9,000 years ago, ancient indigenous peoples domesticated corn and initiated an agricultural revolution, leading to the formation of many complex civilizations.

Between 1,800 and 300 BCE, many matured into advanced pre-Columbian Mesoamerican civilizations such as: the Olmec, Izapa, Teotihuacan, Maya, Zapotec, Mixtec, Huastec, Purepecha, Totonac, Toltec and Aztec: Mexica, which flourished for nearly 4,000 years before the first contact with Europeans.

These civilizations are credited with many inventions and advancements in fields such as architecture (pyramid-temples), mathematics, astronomy, medicine and theology. The Aztecs were noted for practicing human sacrifice on a large scale.

At its peak, Teotihuacan, containing some of the largest pyramidal structures built in the pre-Columbian Americas, had a population of more than 150,000 people. Estimates of the population before the Spanish conquest range from 6 million to 25 million.

At the time of Spanish contact, Teotihuacan was no longer occupied, although the site was well-known; the population of the Aztec Empire and its immediate predecessors had become centered on Lake Texcoco, also in the Valley of Mexico, where the island city of Tenochtitlan was founded in 1325.