Political, economic, and climatic upheaval can result in mass human migration across extreme terrain in search of more humane living conditions, exposing migrants to environments that challenge human tolerance. An empirical understanding of the biological stresses associated with these migrations will play a key role in the development of social, political, and medical strategies for alleviating adverse effects and risk of death. We model physiological stress associated with undocumented migration across a commonly traversed section of the southern border of the United States and find that locations of migrant death are disproportionately clustered within regions of greatest predicted physiological stress (evaporative water loss). Minimum values of estimated evaporative water loss were sufficient to cause severe dehydration and associated proximate causes of mortality. Integration of future climate predictions into models increased predicted physiological costs of migration by up to 34.1% over the next 30 years.