1521年，西班牙人赫爾南·科爾特斯（Hernan Cortes）率軍逐步徵服了墨西哥，並把這裏更名為新西班牙。西班牙王室將土地連同當地印第安人賜給徵服者，實行委托監護製，強迫印第安人服勞役。在接下來的300年當中，作為西班牙的海外殖民地，其主要目的就是生産貴重金屬並供應原料給西班牙製造成品，且提供西班牙工業産品的市場，以使母國富裕並確保自給自足。殖民統治後期，這裏的經濟也有了一定的發展，出現了紡織、皮革、冶煉、釀酒、造船等工業。殖民時期，墨西哥人民曾多次反抗西班牙的統治，到19 世紀初，各種階級矛盾日益激化，獨立的呼聲開始席捲墨西哥。
在這300年中，墨西哥人民一直也沒有停止過反抗殖民統治的鬥爭。直到1821年墨西哥人民纔擺脫西班牙的殖民統治。
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.