Uranium (U) is enriched in the waters of the southern Colorado Plateau, including waters of the Navajo Nation. The region has naturally occurring U in rocks and a history of U mining which may increase U concentrations in waters. Despite prior research into the concentration of U in the waters of the Navajo Nation, a framework has not been established to understand the variation of U in the region’s groundwater. To this end, we examined data from six studies to establish where and why U is likely to be enriched in waters of the southern Colorado Plateau. We show that U concentrations are related to the presence of U-rich rock bodies, elevation, and local aquifer salinity. Additionally, we show that U concentrations in waters downstream from abandoned U mines are higher than in waters that are not downstream from mines, and that the area around mines has an elevated U concentration relative to background U concentrations. Our work can act as a guide for local water withdrawal, regional water remediation and mitigation efforts, and provides a means for understanding the geographical patterns of U concentration in waters of the southern Colorado Plateau.