Orthogneisses derived from granitoids with Variscan protolith ages dominate the lower unit of high-grade metamorphic basement of the Eastern Rhodope Massif in south Bulgaria. We present whole-rock geochemistry and Sr–Pb isotopic composition of these orthogneisses, which are compared with Pb isotopes of parametamorphic rocks, and hydrothermal ore deposits and associated rocks, to better constrain their composition, origin, and contribution to late Alpine hydrothermal processes. The igneous mineral assemblage is partly preserved, and the field textures and microstructures of the orthogneisses are consistent with a ductile, amphibolite-grade tectono-metamorphic overprint during Alpine time, when they were involved in the metamorphic nappe stack. Whole-rock geochemistry revealed compositions of the orthogneisses largely unaffected by the amphibolite-grade metamorphism, displaying a magmatic differentiation trend of the igneous protoliths. The protoliths are peraluminous medium-K calcalkaline S-type granitoids, whose tectono-magmatic setting discrimination consistently indicates a continental volcanic arc origin. The orthogneisses present trace element and rare-earth elements (REE) patterns based on which a group of high-field strength elements-depleted and REE fractionated orthogneisses and a group of LREE-enriched orthogneisses can be distinguished. Both geochemical groups show compositions similar to the bulk and upper continental crust and its sedimentary counterparts. Crustal Pb isotope ratios (206Pb/204Pbi518.24–18.66) of the orthogneisses are comparable to the paragneisses (206Pb/204Pbi518.31–18.93) and uniform in both (207Pb/204Pbi515.64–15.72) and 208Pb/204Pbi ratios in the paragneisses (38.23–38.60) and the orthogneisses (38.32–38.56). The trace element data and 87Sr/86Sri isotopes of the orthogneisses (0.7050–0.7117) overlap those of the parametamorphic rocks (0.7039–0.7144), and confirm the supracrustal origin of the igneous precursors. A heterogeneous crustal source region is suggested in which melting and crustal contamination during magma genesis with subsequent fractional crystallization was involved in the petrogenesis. Comparative Pb isotope systematics suggests that a significant crustal Pb input to ore-forming hydrothermal fluids was derived primarily from the metamorphic basement, implying that the brittlly deformed basement during crustal extension acted as an immediate environment for fluid leaching during late Alpine hydrothermal ore-forming processes.