Tens of millions of people in the Bengal Basin region of Bangladesh and India drink groundwater containing unsafe concentrations of arsenic. This high-arsenic groundwater is produced from shallow (<100 m) depths by domestic and irrigation wells in the Bengal Basin aquifer system. The government of Bangladesh has begun to install wells to depths of >150 m where groundwater arsenic concentrations are nearly uniformly low, and many more wells are needed, however, the sustainability of deep, arsenic-safe groundwater has not been previously assessed. Deeper pumping could induce downward migration of dissolved arsenic, permanently destroying the deep resource. Here, it is shown, through quantitative, large-scale hydrogeologic analysis and simulation of the entire basin, that the deeper part of the aquifer system may provide a sustainable source of arsenic-safe water if its utilization is limited to domestic supply. Simulations provide two explanations for this result: deep domestic pumping only slightly perturbs the deep groundwater flow system, and substantial shallow pumping for irrigation forms a hydraulic barrier that protects deeper resources from shallow arsenic sources. Additional analysis indicates that this simple management approach could provide arsenic-safe drinking water to >90% of the arsenic-impacted region over a 1,000-year timescale. This insight may assist water-resources managers in alleviating one of the world's largest groundwater contamination problems.