Cu-Au skarn deposits of the mining district of Santa María de La Paz are located in the Sierra del Fraile, in the northern part of San Luis Potosí, Mexico. Samples of four different intrusions and their related skarn deposits were taken underground, in order to obtain whole-rock and mineral geochemical data. U-Pb LA-ICP-MS zircon data indicate crystallization ages of ca. 37.6–35.0 Ma for skarn-related granitic and granodioritic stocks, which show dominant metaluminous to slightly peraluminous, high-K calc-alkaline compositions. These intrusions were emplaced in a post-Laramide continental arc setting under shallow conditions, as suggested by fast cooling inferred from K-Ar biotite ages of ca. 35–33 Ma. Skarn deposits were contemporaneous with emplacement and crystallization of stocks, as revealed by Re-Os molybdenite geochronological data of exoskarn rocks. Skarn rocks show a general depletion of LILE and REE and a slightly enrichment in HFSE in comparison with intrusive rocks. Pyroxene and garnet show dominant hedenbergite and andradite compositions, respectively. The association of hedenbergite, pyrite, chalcopyrite, native bismuth and pyrrhotite during skarn mineralization suggest reducing conditions, typical for Au but not for Cu skarns. Highest metal contents are concentrated in exoskarn rocks, including anomalies of Cu, Fe, Ni, Sn, Sb, Zn, W and Bi. Metal contents, ore minerals and environmental conditions of skarn rocks, together with whole-rock geochemical data of stocks and pyroxene-garnet compositions, reveal some singularities for the Sierra del Fraile deposits, as they exhibit characteristics of both Cu and Au skarn deposits but might be also compatible with Fe, W, and Zn skarns. Hence, skarn and associated vein deposits of the Sierra del Fraile might have a high potential not only for Cu-Au, but also for several base metals, as reported for comparable post-Laramide skarn and hydrothermal deposits of central and northern Mexico.