<p>Most giant porphyry-skarn Cu-Au ore systems are associated with either the metasomatic mantle wedge, formed by the dehydration of subducting oceanic crust, or the melting of Cu-rich juvenile lower crust. The ore-forming parent rocks are typically depleted adakites. In contrast, parent rocks in intracontinental Cu-Au ore systems exhibit enriched isotopic compositions, yet their formation mechanisms and deep processes remain unclear. To address this, our study focuses on the central Yangtze River ore belt (CYROB) and adjacent areas. By compiling regional petrological and chronological data, we conducted multi-isotope tracing and Hf isotope mapping, integrated with regional seismic velocity tomography and magnetotelluric detection results, to reconstruct the lithospheric architecture and its evolutionary processes. Our findings indicate that the CYROB underwent significant crustal accretion during the Meso- and Neo-proterozoic, forming a juvenile crust. In the Late Mesozoic, the crust experienced polygenetic reworking, through two distinct periods (156–136 Ma and 136–120 Ma). During the transition from the Late Jurassic to the Early Cretaceous (156–140 Ma), in the area near and north of the Gaotan fault, lithospheric delamination in an extensional setting facilitated mantle convection and partial melting of enriched lithospheric mantle. This process modified the pre-existing juvenile lower crust, leading to the formation of adakites with slightly negative <i>ε</i>_Hf values (−5 to 0) and associated porphyry-skarn Cu-Au deposits. Concurrently, ascent of adakitic magma occasionally incorporated W-rich middle-to-upper crustal materials, enriching the melts in W and forming localized small- to medium-sized skarn W deposits. During 140–136 Ma, with the continued relaxation of lithospheric stress, a more intense modification of the lower crust by enriched mantle occurred west of Anqing and north of Qingyang. This led to the formation of adakic magmas with strongly negative <i>ε</i>_Hf values (−24 to −8) and related skarn Cu-Fe deposits. To the south of the Jiangnan fault, where the crust was deeper, mantle convection induced the remelting of Proterozoic reworked crust, releasing W and Mo into crust-derived melts, ultimately forming a series of large- and medium-sized porphyry-skarn W-Mo deposits. During the late period (136–120 Ma), progressive lithospheric extension triggered large-scale lithospheric delamination and oblique asthenospheric upwelling from the southeast to the northwest, further modifying the lower crust. The remelting of reworked crust with input from depleted mantle materials, led to the formation of extensive alkali-rich granitic batholiths. This study demonstrates that, under the extensional regime of the Late Mesozoic, the polygenic reworking of juvenile crust and the remelting of previously reworked crust—driven by ongoing lithosphere-scale delamination and asthenospheric upwelling—played a key role in controlling the temporal and spatial distribution of metal ore systems in the CYROB and adjacent areas.</p>