Climate change and urbanization are rapidly increasing human exposure to extreme ambient temperatures, yet few studies have examined temperature and mortality in Latin America. We conducted a nonlinear, distributed-lag, longitudinal analysis of daily ambient temperatures and mortality among 326 Latin American cities between 2002 and 2015. We observed 15,431,532 deaths among ≈2.9 billion person-years of risk. The excess death fraction of total deaths was 0.67% (95% confidence interval (CI) 0.58-0.74%) for heat-related deaths and 5.09% (95% CI 4.64-5.47%) for cold-related deaths. The relative risk of death was 1.057 (95% CI 1.046-1.067%) per 1 °C higher temperature during extreme heat and 1.034 (95% CI 1.028-1.040%) per 1 °C lower temperature during extreme cold. In Latin American cities, a substantial proportion of deaths is attributable to nonoptimal ambient temperatures. Marginal increases in observed hot temperatures are associated with steep increases in mortality risk. These risks were strongest among older adults and for cardiovascular and respiratory deaths.