Understanding continental crustal architecture and its control on mineral systems is fundamental to the earth sciences. Here we integrate zircon U-Pb geochronology, whole-rock Nd-Hf isotopes, lithogeochemical data, and regional metallogenic records from Cambrian to Triassic magmatic rocks across the Solonker-Alxa region of Inner Mongolia to define crustal domains and their metallogenic significance. Two contrasting isotopic provinces are identified: (1) an enriched domain [εNd(t) < −4, εHf(t) < 0] encompassing the North China Craton−Alxa Block and (2) a depleted domain [εNd(t) > −4, εHf(t) > 0] typifies the Central Asian orogenic belt (CAOB). These domains are separated by the Chifeng-Bayan Obo fault, the area north of Chaganhua, and the Quagan Qulu-Tebai fault. Crustal thickness patterns show a belt of thinned crust (<40 km) along the Mandula, Solonker, Ganqimandu, Yingba, and northern Enger Us fault zones, marking the boundary between the Mongolia collage and the Tarim-North China collage. Variations in crustal thickness suggest that the Alxa Block is a distinct Precambrian terrane, separate from the North China Craton. The protracted subduction-accretion and slab rollback of the Paleo-Asian Ocean have driven significant crustal growth in the Solonker-Alxa region, with juvenile crust contributions estimated at 37% in the southern CAOB. Crustal maturation and felsic differentiation resulted from polyphase melting events involving mafic lower crust, oceanic crust, and the middle to upper crust. A systematic correlation exists between isotopic domains, crustal architecture, and metallogenic distribution. Depleted domains with thin crust (<50 km) preferentially host porphyry Cu (± Au), epithermal Pb-Zn-Cu, and volcanic massive sulphide-type Cu deposits, whereas enriched isotopic domains and their peripheries contain porphyry Mo, skarn Cu-Fe, vein-type Au deposits, and magmatic Cu-Ni sulfide deposits, indicating genetic links to ancient crustal recycling and metasomatized lithospheric mantle. This synthesis provides a coherent tectono-metallogenic framework for the Solonker-Alxa segment of the southern CAOB and offers guidance for mineral exploration.