Elevated arsenic exposure from drinking water is associated with an increased risk of cardiovascular disease, diabetes, kidney disease, and skin, lung, and bladder cancer. Arsenic contamination in groundwater supplies disproportionately affects rural populations using private wells. Arsenic mitigation programs for American Indian communities are limited. There is an urgent need for targeted approaches to reduce arsenic exposure for at-risk communities using private wells. Formative research was conducted to inform and design a community-based arsenic mitigation intervention for Lakota and Dakota Nations in the Great Plains Area of the United States, where, in some communities, one-quarter of private wells are estimated to have elevated arsenic. Formative research included semi-structured interviews, a community workshop, intervention-planning workshops, and a pilot study of the developed intervention. Community members prioritize aesthetic qualities of water (e.g. taste, color), safety, and other situational factors (e.g. cost) when considering their drinking and cooking water. Although water safety is a concern, awareness and concern for arsenic vary substantially within communities. To reduce arsenic exposure, community members recommended communication of water test results, home visits for intervention delivery, and reminders to use arsenic-safe water. Findings informed the development of an intervention to prevent arsenic exposure through drinking water and cooking, including health promotion messages and household items to facilitate use of an arsenic removal device (e.g. tankards to store filtered water). The pilot study indicated promising acceptability and operability of the developed intervention. This research provides a model for the development of environmental health interventions in partnership with American Indian and other private well-using communities.