The unique ore-forming processes and the key factors responsible for formation of skarn deposits are still obscure, and challenges exist in the determination of timing of Pb-Zn skarns owing to lacking suitable mineral chronometers. Here we present detailed paragenesis, bulk geochemistry, in situ U-Pb dating of zircon and garnet, and garnet oxygen isotopes together with in situ zircon Hf-O isotopes from the newly discovered Aqishan Pb-Zn deposit in the southern Central Asian Orogenic Belt (CAOB), northwest China. This comprehensive data set revealed a Late Carboniferous subduction-related distal Pb-Zn skarn system associated with the granitic magmatism. Pre-ore stage garnets are generally subhedral to euhedral with oscillatory zoning and show slightly fractionated rare earth element patterns with positive Eu anomalies that point to an infiltration metasomatism origin under high water/rock ratios. The syn-ore stage sphalerite is typically enriched in Mn and Cd and has moderate Zn/Cd ratios (337–482), with a formation temperature of 265 °C to 383 °C, which indicate magmatic-hydrothermal signatures. The isocons defined by P2O5 decipher that the principal factors for skarn formation were elevated activities of Fe, Ca, and Si species, where remobilization of Pb metals, meanwhile, contributed to ore-forming budgets to mineralizing fluids. SIMS U-Pb dating of zircons from granite porphyry that occurs distal to the skarns and Pb-Zn orebodies shows that these intrusions emplaced at ca. 311.3–310.6 Ma, recording the subduction of the Paleo-Tianshan oceanic plate. Hydrothermal garnets in close textural association with Pb-Zn sulfides yield indistinguishable in situ LA-ICP-MS U-Pb ages of 310.5 ± 4.1 Ma. Whole-rock geochemistry and in situ zircon Hf-O isotopes (δ18O = 4.6‰–6.0‰) indicate that the granite porphyry was derived from partial melting of juvenile crust and influenced by subducted oceanic crust. Oxygen isotope compositions of garnets (δ18O = 8.0‰–9.0‰) demonstrate that the equilibrated ore fluids were inherited from fluid-rock interactions between a primary magmatic water and host tuff rocks. Our study highlights the application of garnets as a potential robust U-Pb geochronometer and isotopic tracer of ore fluids in skarn mineralizing systems in subduction-related arc environments.