The Paramillos de Uspallata deposit, previously considered as genetically linked to a Miocene porphyry deposit, is located in the Mesozoic Cuyo Basin, which was formed during the beginning of the break-up of Gondwana. In the present study, both previous information and new geological, mineralogical, and isotopic data allowed outlining a new descriptive model for this deposit. Stratigraphic and structural controls allowed considering this deposit as contemporaneous with the Mesozoic rifting, with the mineralization resulting from a Pb–Zn stage followed by an Ag–Cu–Pb stage. The hydrothermal fluids were found to have low temperature and low to moderate salinity, and to result from the mixing between metamorphic and meteoric fluids, with the lead sourced by the igneous Paleozoic basement and the sulfur partly derived from a magmatic source. These characteristics allow describing Paramillos de Uspallata as Pb–Zn–Ag veins hosted in clastic sedimentary sequences genetically linked to a rift basin and redefining it as detachment-related mineralization.