Well water around the world can be contaminated with arsenic, a naturally occurring geological element that has been associated with myriad adverse health effects. Persons obtaining their drinking water from private wells are often responsible for well testing and water treatment. High levels of arsenic have been reported in well water-supplied areas of the United States. We quantified – in cases and dollars – the potential burden of disease associated with the ingestion of arsenic through private well drinking water supplies in the United States. To estimate cancer and cardiovascular disease burden, we developed a Monte Carlo model integrating three input streams: (1) regional concentrations of arsenic in drinking water wells across the United States; (2) dose–response relationships in the form of cancer slope factors and hazard ratios; and (3) economic cost estimates developed for morbidity endpoints using ‘cost-of-illness’ methods and for mortality using ‘value per statistical life’ estimates. Exposure to arsenic in drinking water from U.S. domestic wells is modeled to contribute 500 annual premature deaths from ischemic heart disease and 1,000 annual cancer cases (half of them fatal), monetized at $10.9 billion (2017 USD) annually. These considerable public health burden estimates can be compared with the burdens of other priority public health issues to assist in decision-making.