The Huoshaoyun deposit in the Karakorum area of NW China is the world’s largest zinc-lead carbonate ore deposit. Here we investigate the genesis of the mineralization based on multiproxy investigations. The deposit contains zinc-lead carbonate and sulfide minerals, with smithsonite (Smt), cerussite (Cer), and sulfides accounting for 85%, 10%, and 5% of the total lead and zinc resources, respectively. Three ore-forming stages, involving Smt, Cer, and sulfides ores were summarized. The Smt mineralization is characterized by veined, massive, and stratified Smt forming horizontal sedimentary layered ore and vertical feeder veins similar to the SEDEX-type deposits. The sulfide and Cer veins display typical hydrothermal characteristics and are superimposed on the massive Smt ores. The Smt ores show high Li, Be, Cr, Y, Ba, Nd, Yb, and Zr contents, whereas the Cer veins have extremely high Sr contents (up to 3814–9174 ppm) and low Zr contents (less than 0.01 ppm). Galena and sphalerite show higher Cd concentrations compared to Smt and Cer ores.The Smt ores differ with different spatial locations, with Smt ores formed at the vent have δ66Zn values of +0.15‰ to +0.21‰, the massive Smt formed close to the vent show a value of +0.13‰, and those formed away from the vent show a value of 0.05‰, all values being close to 0. The sulfides have δ66Zn values of −0.09‰ to +0.04‰. The C-O isotopes of Smt ores are similar to both altered and unaltered host limestone, suggesting that the limestone was a potential source for carbon and oxygen. Quartz with veined Smt shows magmatic signatures with δ18OVSMOW of +1.14‰ to +2.23‰, high Pb (115–401 ppm) and Zn concentrations (390–997 ppm), whereas quartz associated with sulfide has meteoric fluid signature with the lowest δ18OVSMOW (−14‰ to −10.7‰), low Pb (11.6–49.0 ppm) and Zn (18.1–72.8 ppm) concentrations. The temperature of equilibration computed based on oxygen isotope fractionation between Smt and coeval quartz indicate a dual source with that of quartz derived from an aqueous fluid, whereas the source for Smt might involve CO2 or HCO3−.We trace multiple metallogenic stages for this deposit including exhalation, hydrothermal deposition, and fault-controlled sulfide vein formation. The largest orebody (III-1) preserves a 16 Mt reserve of Zn and was formed by crust-mantle interaction at ca. 195 Ma in the early development of the Linjitang post-arc rift system. Fluid convection, zinc enrichment driven by granitic magma, volcanic activity, and karst alteration induced by acid rain in a lagoonal environment promoted ore enrichment.