A multiparameter geochemical-isotopic fingerprinting approach was used to differentiate natural and anthropogenic signatures of uranium contamination near the Homestake uranium mill site (Site), near Milan, New Mexico, USA. The Site consists of two tailings piles from milling operations and groundwater contamination from these tailings have been noted. The Site lies within the lower San Mateo Creek Basin with multiple regional sources of U contamination from mining and mill operations and is underlain by a heterogeneous alluvial aquifer, which is underlain by basement rock of the Chinle Group and the lowermost San Andres-Glorieta aquifer. To help decipher signatures, several statistical approaches were used including PCA, NMDS, and cluster analysis. Trilinear piper diagrams indicate two end member water types at the Site, sulfate-Na-K and sulfate-Ca. Natural alluvial aquifer groundwater in this area, relatively unaffected by mining or milling, appears to be more dominated by bicarbonate than sulfate and the deeper San Andres-Glorieta aquifer that has a mixture of sulfate and bicarbonate. Uranium concentrations from the Site fall into three broad categories, less than the drinking water standard of 30 µg/L (n=3), from 30 to 100 µg/L (n=9) and greater than 100 µg/L (n=8). Component loadings in a principal component analysis are highest for uranium isotopes, 228Ra, gross alpha-beta, molybdenum, chloride, uranium, and sodium, which affect the similarities or differences among wells sampled. Results suggest that several alluvial wells upgradient from the Site have anthropogenic fingerprints from regional sources related to upgradient mining. Wells with higher uranium concentrations have uranium activity ratios close to 1, which is indicative of mining or milling signatures. These same wells have elevated radon activities. This information can be used to inform Site managers on the source of water related to uranium at the Site and provide an approach for geochemical fingerprinting.