Abstract Uranium and As in deep groundwater of the volcano-sedimentary Villa de Reyes Graben around the city of San Luis Potosí in semi-arid North-Central Mexico (mean U: 7.6μgL−1, max. 138μgL−1; mean As: 11.4μgL−1, max. 25.8μgL−1) partly exhibit concentrations in excess of the WHO guideline values and thus endanger the quality of the most important drinking water source. To unravel the mechanisms for their enrichment in groundwater, the potential trace element sources, volcanic rocks and basin fill sediments, were characterized. A total of 131 solid and liquid samples were analyzed for major and trace element composition. The As/U hydrogeochemical signatures, their behavior during rock alteration and evidence from other major and trace element distributions, especially rare earth elements, strongly argue for dissolution of acid volcanic glass to be the dominating process of U and As release into groundwater. This natural baseline quality representing water–acid volcanic rock interaction is modified by additional trace element (preferentially As) mobilization from the sedimentary basin fill, representing a secondary source, in the course of decarbonatization of playa lake sediments and desorption from Fe-(hydr)oxide coated clastic material. The common behavior of both elements during magmatic differentiation and growing drift apart in sedimentary environments are important findings of this work. Comparison with recent findings in a similar environment suggests a common primary trace element source identification but significant differences in the evolution of As and U distribution. Geological and climatic similarity to numerous volcano-sedimentary basins makes the findings useful for water management purposes and transferable to other semi-arid regions facing challenges of geogenically impacted drinking water quality.