During the Spanish conquest of the Aztec Empire, Tlaxcala allied with the Spaniards against the Aztecs, supplying a large contingent for – and at times the majority of – the Spanish-led army that eventually destroyed the Aztec empire.
The Tlaxcalans arrived in Central Mexico during the Late Postclassic. They first settled near Texcoco in the valley of Mexico, between the settlement of Cohuatlinchan and the shore of Lake Texcoco.  After some years the Tlaxcallans were driven out of the valley of Mexico and moved to the east, splitting into three groups along the way. While one group continued north towards the modern state of Hidalgo and another remained in the vicinity of Texcoco, a third group arrived to the modern valley of Tlaxcala, where they established the city of Tepetícpac Texcallan under the leadership of Culhuatecuhtli Quanex.
Over the subsequent years, the Tlaxcallan state expanded with the foundations of Ocotelulco and Tizatlán. The fourth major settlement, Quiahuiztlan, was founded by members of the Tlaxcallan group that had initially remained in the valley of Mexico. 
Ancient Tlaxcala was a republic ruled by a council of between 50 and 200 chief political officials (teuctli [sg.], teteuctin [pl.]) (Fargher et al. 2010). These officials gained their positions through service to the state, usually in warfare, and as a result came from both the noble (pilli) and commoner (macehualli) classes.
Tlaxcala was never conquered by the Aztec empire, but was engaged in a state of perpetual war, the so-called flower wars or garland wars.
As a result of their alliance with the Spaniards, Tlaxcala had hidalgo privileged status within Spanish colonial Mexico. After the Spanish conquered Tenochtitlan and the rest of Mexico, Tlaxcala was allowed to survive and preserve its pre-Columbian culture. In addition, as a reward to the Tlaxcalans unyielding loyalty to the Spanish, the city and its inhabitants largely escaped the pillaging and destruction following the Spanish conquest.
Conquistador Bernal Díaz del Castillo describes the first battle between the Spanish force and the Tlaxcalteca as surprisingly difficult. He writes that they probably would not have survived, had not Xicotencatl the Elder, and Maxixcatzin, persuaded Xicotencatl the Younger - the Tlaxcallan warleader- that it would be better to ally with the newcomers than to kill them. : 140–188
Due to protracted warfare between the Aztecs and the Tlaxcala, the Tlaxcala were eager to exact revenge, and soon became loyal allies of the Spanish. Even after the Spanish were expelled from Tenochtitlan, the Tlaxcala continued to support their conquest. Tlaxcala also assisted the Spanish in the conquest of Guatemala.
Following the Spanish Conquest, Tlaxcala was divided into four fiefdoms (señoríos) by the Spanish corregidor Gómez de Santillán in 1545 (26 years after the Conquest). These fiefdoms were Ocotelolco, Quiahuiztlan, Tepeticpac, and Tizatlan. At this time, four great houses or lineages emerged and claimed hereditary rights to each fiefdom and created fictitious genealogies extending back into the pre-Columbian era to justify their claims (Gibson 1952).
During the colonial period, the Tlaxcalan people were regarded as being of higher status and received better treatment compared to the other indigenous peoples of New Spain. However, the indigenous population who had been living in Tlaxcala were reduced to a small minority. According to the Catholic Encyclopedia , in 1625 the city of Tlaxcala had only 700 people, compared to a population of 300,000 a century earlier, owing to epidemics, emigrations, and the work of digging the canal of Nochistongo to drain the Valley of Mexico.