Average and extreme temperatures will increase in the near future, but how such shifts will affect mortality in natural populations is still unclear. We used a dynamic model to predict mortality under variable temperatures on the basis of heat tolerance laboratory measurements. Theoretical lethal temperatures for 11 Drosophila species under different warming conditions were virtually indistinguishable from empirical results. For Drosophila in the field, daily mortality predicted from ambient temperature records accumulate over weeks or months, consistent with observed seasonal fluctuations and population collapse in nature. Our model quantifies temperature-induced mortality in nature, which is crucial to study the effects of global warming on natural populations, and analyses highlight that critical temperatures are unreliable predictors of mortality.