The Huoshaoyun carbonate-hosted non-sulfide Zn–Pb deposit in the Karakoram area, northwest China, provides an excellent setting for investigating the origin of this type of deposit. Here, geology, mineralogy, elements, and C–O–S–Pb isotopes evidence are presented to constrain the ore genesis of the Huoshaoyun deposit. Two orebodies occur in limestone of the Longshan Formation, which exhibit laminated, banded, and brecciated textures. Ore minerals of the Huoshaoyun deposit are dominated by smithsonite and cerussite, with subordinate galena and pyrite. From early to late, ore formation is divided into three stages, which are sulfide stage, oxidation stage I and oxidation stage II. The C–O isotopic compositions of smithsonite (δ13CPDB: –0.70‰ to 4.50‰, δ18OSMOW: 23.30‰ – 25.20‰), cerussite (δ13CPDB: –3.00‰ to –1.80‰, δ18OSMOW: 10.60‰ to 13.10‰), mineralization stage calcite (δ13CPDB: 0.90‰ to 2.80‰, δ18OSMOW: 12.40‰ to 24.80‰) and calcite within wall-rocks (δ13CPDB: –0.30‰ to 2.60‰, δ18OSMOW: 13.20‰ to 25.60‰) indicate that the carbon and oxygen source of the Huoshaoyun deposit are closely related to the sedimentary strata, and the minerals have experienced intense TSR effect of organic matter and influenced by meteoric water to a greater extent. Compared with gypsum in the Longshan Formation (δ34SV-CDT: 17.10‰ and 17.20‰) and veined gypsum near the orebodies (δ34SV-CDT: –26.30‰ to –18.50‰), galena and pyrite both enrich negative sulfur isotopes with δ34SV-CDT values ranging from –35.60‰ to –13.00‰, which reveal that the sulfur in the Huoshaoyun deposit was derived from low-temperature bacterial reduction of evaporative sulfate. The uniform Pb isotopic data of galena, cerussite, and anglesite (208Pb/204Pb: 38.857 – 38.935, 207Pb/204Pb: 15.677 – 15.694, 206Pb/204Pb: 18.515 – 18.552) from the Huoshaoyun deposit display linear trends in Pb isotope diagrams, which imply that the galena, cerussite, and anglesite should have been exposed to a series of cogenetic evolutionary processes and shared the same lead sources with significant upper crust and orogenic contribution. In comparison with Pb isotopic data of regional strata (208Pb/204Pb: 38.530 – 39.695, 207Pb/204Pb: 15.579 – 15.883, 206Pb/204Pb: 18.290 – 20.035), the combination of these regional strata can provide the enough metals for mineralization and induce the Pb isotopic characteristics evolving to the present model in the Huoshaoyun deposit. In summary, the ore-forming materials are mainly sourced from regional strata, and the Huoshaoyun deposit is a supergene MVT deposit-a new non-sulfide deposit type in China.