The Guanting Pb–Zn deposits in the Jianshui area, southern Yunnan Province, SW China, are located in the conjunction of the Yangtze Block, Cathaysian Block and Sanjiang Block, and they belong to part of the Sichuan-Yunnan-Guizhou (SYG) Pb–Zn metallogenic province. The Pb–Zn orebodies occur in basaltic and limestone breccia at the interfaces between the Maokou limestone and Emeishan basalt. Here, we use zircon U–Pb dating, Rb–Sr dating, trace elements and S isotope data of sulfides to constrain the ages and genesis of deposits. Petrological investigations reveal two main stages of mineralization. Early-stage sphalerites yield a Rb–Sr age of 251.1 ± 8.5 Ma, and it is contemporaneous with the Guanting basalt within the range of error, which has a concordant age of 247.3 ± 4.2 Ma. This metallogenic age indicates that early-stage mineralization may be related to Emeishan volcanic hydrothermal activity. Initial value of 87Sr/86Sr (0.709) and rare earth elements (REE) patterns of minerals suggest that ore-forming materials were likely derived from mixed mantle-crust sources, and paleo-seawater participated in deposition of Pb–Zn ore. There are two peaks of sulfur isotope (δ34S) in the Huangtian and Xinzhai deposits. The δ34S of early-stage sulfide is concentrated at + 1.1‰ VCDT to + 3.9‰ VCDT, suggesting that the sulfur was directly supplied by basaltic volcanic activity. Late-stage colloidal sulfides have δ34S ranging from + 6‰ VCDT to + 9‰ VCDT, suggesting marine sulfur origin, and that reduced sulfur derived from carbonate strata by thermochemical sulfate reduction (TSR). According to the geochemical characteristics, geochronology and regional geodynamic setting, we assume that early-stage mineralization in the Guanting Pb–Zn deposits is Emeishan volcanic hydrothermal mineralization, and late-stage mineralization is similar with Mississippi Valley-type (MVT) deposit. Our results provide new evidence for understanding hydrothermal mineralization associated with the Emeishan flood basalts in the SYG area.