1521年，西班牙人赫尔南·科尔特斯（Hernan Cortes）率军逐步征服了墨西哥，并把这里更名为新西班牙。西班牙王室将土地连同当地印第安人赐给征服者，实行委托监护制，强迫印第安人服劳役。在接下来的300年当中，作为西班牙的海外殖民地，其主要目的就是生产贵重金属并供应原料给西班牙制造成品，且提供西班牙工业产品的市场，以使母国富裕并确保自给自足。殖民统治后期，这里的经济也有了一定的发展，出现了纺织、皮革、冶炼、酿酒、造船等工业。殖民时期，墨西哥人民曾多次反抗西班牙的统治，到19 世纪初，各种阶级矛盾日益激化，独立的呼声开始席卷墨西哥。
在这300年中，墨西哥人民一直也没有停止过反抗殖民统治的斗争。直到1821年墨西哥人民才摆脱西班牙的殖民统治。
The Spanish defeat of the Aztecs in 1521 marked the beginning of the 300 year-long colonial period called the New Spain. After the fall of Tenochtitlan, it would take decades of sporadic warfare to pacify the rest of Mesoamerica. Particularly fierce was the Chichimeca War in the north of the New Spain (1576-1606).
The Council of Indies and the Mendecant establishments that arose in Mesoamerica as early as 1524 labored to generate capital for the broken crown of Spain and convert the Indian populations to Catholicism. Over the period of conquest (1519-c1600s) and the following Colonial periods the sponsorship of Mendecant friars and a process of religious syncretism combined the Pre-Hispanic cultures with Spanish socio-religious tradition. The resulting hodgepodge of culture was a pluriethnic State that relied on the repartimiento of peasant "Republic of Indians" labor to accomplish any work considered necessary. The existing feudal system of pre-Hispanic Mesoamerican culture was replaced by the encomienda feudal-style system of Spain, probably adapted to the pre-Hispanic tradition. It was finally replaced by a debt-based inscription of labor that led to wide-spread revitalization movements and prompted the revolution that ended the colonial state of New Spain.
During the colonial period, which lasted from 1521 to 1810, Mexico was known as "la Nueva España" or "New Spain" (as aforementioned), whose territories included today's Mexico. ("Mexico" in this period only meant the area that is the Valley of Mexico.) This entity was part of an eponymous viceroyalty, which joined with it the Spanish Caribbean islands, Central America as far south as Costa Rica, the area comprising today's southwestern United States, and the Philippines. Since Spaniards conquered areas with high civilizations and dense populations, which could provide the settlers with a sufficient labor source and a population to catechize, Spaniards in the sixteenth century tended not to develop the territories that had nomadic peoples, which were harder to conquer (and in fact, with the exception of the Amazon Basin, were not subdued until the nineteenth century). The Spanish did explore a good part of North America looking for more treasure-laden societies. These explorers claimed the land as was their practice, but finding no treasures or sedentary Indian tribes, they returned to the areas in Mexico, which had already been conquered. It was in the seventeenth century that a concerted effort was made to settle the northern frontier in what is now the United States.