Talc alteration is a characteristic feature of various ore deposit types, including magmatic, hydrothermal, and metamorphic systems. In the Arabian-Nubian Shield (ANS), the Derhib deposit within the Shadli Metallogenic Belt (South Eastern Desert, Egypt) represents a complex auriferous sulfide-talc system. Despite historical mining interest, the deposit remains underexplored using advanced analytical techniques, hindering our understanding of the physiochemical conditions and mechanisms governing ore precipitation. An integrated approach combining intensive field observations, petrographic investigations, and geochemical-isotopic analyses (whole rock geochemistry, U-Pb-Lu-Hf geochronology, zircon and sulfide chemistry, and S isotopes) was employed. Rhyolitic lavas in the Derhib shear zone exhibit calc-alkaline, metaluminous to peraluminous compositions, enriched in Ba, Th, Nd, U, Zr, and Sm but depleted in Nb, Ta, P, and Sr, reflecting subduction-related island-arc magmatism. Field relationships and geochemical signatures indicate a carbonate protolith for the Derhib talc deposit, evidenced by (a) the presence of chlorite adjacent to dolomite, (b) low Cr, Ni, and Co concentrations, (c) positive correlations between Sigma REE and Zr, Hf, and Th, (d) similarities in REE patterns between talc ore and sedimentary samples, (e) a Y/Ho ratio in the talcose rocks aligns with carbonates rocks, (f) REE depletion inherited from carbonate units, and (g) the absence of VMS alteration zones. Magmatic zircon ages from highly sheared rhyolitic lava are largely consistent with the Shadli metavolcanics (similar to 695 Ma), while recrystallized zircons yield a concordia age of 137.5 +/- 1.1 Ma, attributed to Upper Cretaceous volcanic episodes in the Egyptian Eastern Desert. Zircon trace elements, initial epsilon Hf(t) values (-10.5 to -17.8), and Hf crustal model ages (1.68 Ga to 2.15 Ga) indicate significant crustal involvement in their genesis. Additionally, the mineral chemistry of sulfide, chlorite, and talc, along with the sulfide delta S-34 values (-7.57 parts per thousand to +3.48 parts per thousand), reveals that the sulfides associated with highly deformed talc-rich rocks display epigenetic features, suggesting sulfur contribution from country rocks through remobilization of pre-existing sulfide ores. Structural lineaments acted as channels for mineralizing fluids, creating favorable sites for metal precipitation during ANS crustal evolution. This study provides valuable insights into the geological and geochemical processes shaping the Derhib sulfide-talc deposit. However, further geochronological and isotopic investigations are needed to fully constrain paragenetic sequence and ore genesis.