The simultaneous occurrence of uranium (U), fluoride (F−), and arsenic (As) in groundwater has become a significant concern in many parts of the world. Although these elements differ in their mineral sources and geochemical behavior, field observations consistently show that they appear together in specific geological and climatic settings. This is not coincidental. Instead, it reflects a natural geochemical alignment shaped by lithology, climate, and long-term interactions between water and rock. U is typically derived from granitic and volcanic rocks, fluoride from fluorite and F-rich silicates, and As from sulfide minerals and iron oxides. Redox conditions, pH, and carbonate availability strongly influence their release. In semiarid regions, long groundwater residence times and high evaporation rates promote alkaline, sodium–bicarbonate waters that enhance fluorite dissolution, stabilize uranyl–carbonate complexes, and favor the reductive release of arsenic. This chapter summarizes the geological settings, mobilization pathways, and global hotspots where U–F−–As coexist. Understanding this natural alignment provides a basis for predicting vulnerable aquifers and designing more effective groundwater monitoring and management strategies.