Background: Every day, billions of people - especially those living in poverty - are exposed to infectious pathogens in the environment and are at risk of contracting 'environmentally mediated' infections: those with environmental reservoirs that affect disease persistence and control. The complex ecology of environmental pathogens creates a global health problem not easily solved with medical treatment alone. Methods: Here, we quantified the global disease burden caused by environmentally mediated infections and used a structural equation modeling approach to explore correlated factors at the global scale. Findings: We found that 80% of pathogen species known to infect humans are environmentally mediated, causing about 40% of today's burden of infectious disease (global loss of 130 million years of healthy life annually). More than 91% of environmentally mediated burden occurs in tropical countries, and the poorest countries carry the highest burdens across all latitudes. We found weak or absent effects of biodiversity or agricultural land use at the global scale. In contrast, the strongest proximate indicator of environmentally mediated infectious disease burden is rural poor livelihoods. Political stability and wealth are associated with improved sanitation, better health care, and lower proportions of rural poor people, indirectly resulting in lower burdens of environmentally mediated infections. 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 Statement: SHS, IJJ, and GADL received support from the Stanford Institute for Innovation in Developing Economies Global Development and Poverty Initiative. SHS and GADL also received support from the Bill & Melinda Gates Foundation (OPP1114050), National Institutes of Health (NIH) grant #1R01TW010286, National Science Foundation Coupled Natural and Human Systems grant #1414102, and the National Institute for Mathematical and Biological Synthesis through the Working Group Optimal Control of Neglected Tropical Diseases.” IJJ was also funded by National Science Foundation Graduate Research Fellowship #1656518. SHS, SRH, CLW, KDL, MBonds, and GADL were supported by a grant from the National Center for Ecological Analysis and Synthesis through the Science for Nature and People Partnership program. AJL was supported by the Davis Family E-IPER Fellowship at Stanford and the Stanford Interdisciplinary Graduate Fellowship from the Stanford Vice Provost for Graduate Education. NN was supported by the Stanford Bing Fellowship in Honor of Paul Ehrlich. CLW was supported by a Sloan Research Fellowship from the Alfred P. Sloan Foundation and by the Michigan Society of Fellows at the University of Michigan. AJP was supported by a Queensland Government Accelerate Postdoctoral Research Fellowship and the DARPA PREEMPT program Cooperative Agreement # D18AC00031. Declaration of Interests: The authors declare no competing interests.