Arc-related volcanism results from the interplay of magmatic processes occurring in trans-crustal systems that consolidate over time in a given location. Trans-crustal systems comprise extensive networks of magma reservoirs and conduits at different depths, wherein melts cyclically differentiate and segregate before reaching the surface. The study of these systems provides valuable insights into crustal-scale phenomena, such as the evolution of the continental crust and the formation of metallogenic regions. In this study, we address the trans-crustal magmatic evolution of lower Miocene magmatism parental to several intermediate-sulfidation epithermal deposits in the eastern Sierra Madre del Sur igneous province, southern Mexico. Using a multi-methodological approach, we document changes over ca. 1.1 M.yr. in the magmatic system that fed andesitic-to-felsic volcanism in this region. We employ whole-rock REE ratios and λ parameters—which are used to quantify the shape of a REE pattern—to track the involvement of pressure-sensitive minerals in the deep-crustal magmatic evolution. The andesitic rocks consist of lava flows, porphyries, and dikes that collectively show REE patterns suggestive of control by fractionated or residual (i.e., in crustal melting) amphibole and/or clinopyroxene. In contrast, the felsic rocks consist of rhyolitic–dacitic ignimbrites, domes, and dikes that show contrasting REE patterns suggestive of control by plagioclase, clinopyroxene, amphibole, and/or garnet. The distinct pressure-sensitive mineral assemblages in the andesitic and felsic rocks indicate that the locus of deep-crustal magma evolution varied within the middle–lower crust. These magmas were episodically injected into ephemeral shallow crustal reservoirs (shortly?) before being erupted, inducing a progressive thermomechanical maturation of the middle–upper crust. Meanwhile, low degrees of crustal assimilation occurred as recorded by Mesozoic inherited zircon ages and Sr–Nd–Pb radiogenic isotopes. An extensive middle–lower crustal magma evolution has been linked to the formation of porphyry Cu deposits (i.e., ‘fertile’ magmatism). Given that intermediate-sulfidation epithermal deposits may be genetically linked with porphyry Cu deposits, the documented processes could have contributed to the formation of epithermal deposits in the region. However, magmatic fertility proxies resemble those from infertile magmas worldwide. Since these proxies have been exclusively applied to porphyry-type deposits, our results highlight the importance of developing new geochemical exploration tools applicable to a wider range of ore deposits.