It is well-established that the Conquest of the Americas by Europeans led to catastrophic declines in indigenous populations. However, less is known about the conditions under which indigenous communities were able to overcome the onslaught of disease and violence that they faced. Drawing upon a rich set of sources, including Aztec tribute rolls and early Conquest censuses (chiefly the Suma de Visitas (1548)), we develop a new disaggregated dataset on pre-Conquest economic, epidemiological and political conditions both in 11,888 potential settlement locations in the historic core of Mexico and in 1,093 actual Conquest-era city-settlements. Of these 1,093 settlements, we show that 36% had disappeared entirely by 1790. Yet, despite being subject to Conquest-era violence, subsequent coercion and multiple pandemics that led average populations in those settlements to fall from 2,377 to 128 by 1646, 13% would still end the colonial era larger than they started. We show that both indigenous settlement survival durations and population levels through the colonial period are robustly predicted, not just by Spanish settler choices or by their diseases, but also by the extent to which indigenous communities could themselves leverage nonreplicable and nonexpropriable resources and skills from the pre-Hispanic period that would prove complementary to global trade. Thus indigenous opportunities and agency played important roles in shaping their own resilience.