Background: Billions of people living in poverty are at risk of environmentally mediated infectious diseases—that is, pathogens with environmental reservoirs that affect disease persistence and control and where environmental control of pathogens can reduce human risk. The complex ecology of these diseases creates a global health problem not easily solved with medical treatment alone. Methods: We quantified the current global disease burden caused by environmentally mediated infectious diseases and used a structural equation model to explore environmental and socioeconomic factors associated with the human burden of environmentally mediated pathogens across all countries. Findings: We found that around 80% (455 of 560) of WHO-tracked pathogen species known to infect humans are environmentally mediated, causing about 40% (129 488 of 359 341 disability-adjusted life years) of contemporary infectious disease burden (global loss of 130 million years of healthy life annually). The majority of this environmentally mediated disease burden occurs in tropical countries, and the poorest countries carry the highest burdens across all latitudes. We found weak associations between disease burden and biodiversity or agricultural land use at the global scale. In contrast, the proportion of people with rural poor livelihoods in a country was a strong proximate indicator of environmentally mediated infectious disease burden. Political stability and wealth were associated with improved sanitation, better health care, and lower proportions of rural poverty, indirectly resulting in lower burdens of environmentally mediated infections. Rarely, environmentally mediated pathogens can evolve into global pandemics (eg, HIV, COVID-19) affecting even the wealthiest communities. Interpretation: The high and uneven burden of environmentally mediated infections highlights the need for innovative social and ecological interventions to complement biomedical advances in the pursuit of global health and sustainability goals. Funding: Bill & Melinda Gates Foundation, National Institutes of Health, National Science Foundation, Alfred P. Sloan Foundation, National Institute for Mathematical and Biological Synthesis, Stanford University, and the US Defense Advanced Research Projects Agency.