The Maoping Devonian and Carboniferous carbonate-hosted epigenetic Pb-Zn deposit, a typical representative of multi-layer (two or more than two ore-bearing strata) Pb-Zn metallogenesis, is located in the central Upper Yangtze Pb-Zn metallogenic province, which consists of > 400 carbonate-hosted Pb-Zn deposits (spots) accounting for at least a quarter of total Pb and Zn reserves in China. The Maoping deposit is the second largest one in the province and contains similar to 30 Mt ores with grades of Pb + Zn ranging from 15 wt% to 35 wt%. A total of three ore bodies (groups) as layers, lens or veinlets are distributed in the NW-trending inverted wing of the Maomaoshan anticline and its secondary NE-trending bedding fracture. Nos. I, II and III ore bodies (groups) are hosted by dolostone of the late Devonian Zaige Fm., early Carboniferous Baizuo Fm., and late Carboniferous Weining Fm., respectively. Sphalerite, galena and pyrite are the most abundant sulfide minerals, while dolomite, calcite, quartz and barite are gangue minerals. These minerals have a massive, disseminated or veined structure, and a granular, metasomatic, co-edge, colloidal, aggregate or fragmentation texture, suggesting an epigenetic origin. NanoSIMS in-situ sulfur isotope analysis shows that the OS values of sulfides ranging from - 20.4 parts per thousand to + 25.7 parts per thousand, of which the pyrite framboid and colloidal sphalerite have delta S-34 values ranging from - 20.4 parts per thousand to - 8.7 parts per thousand, and the delta S-34 values of euhedral granular pyrite and xenomorphic granular sphalerite vary from + 22.1 parts per thousand to + 25.7 parts per thousand. Such sulfur isotope signatures indicate that the formation of S2- in ore-forming fluids has undergone both marine bacterial sulfate reduction (BSR) and thermochemical sulfate reduction (TSR) processes. The processes of BSR and TSR are chiefly temperature depended, so the reduction of sulfate in the Maoping deposit is most likely to occur at the local and may first undergo a relatively low temperature's BSR process, then goes through a relatively high temperature's TSR process. LA-MC-ICPMS in-situ Pb isotope analysis shows that the Pb isotopic ratios of galena are relatively uniform and Pb-206/Pb-204 = 18.707-18.773, (207)pb/(204)pb = 15.780-15.802 and Pb-208/Pb-204 = 39.375-39.530. Such Pb isotope signatures indicate that the source of Pb is single or well-mixed. After comparing with all the potential metal source rocks, we implied that the metals in the Maoping deposit were mainly derived from wall rocks with a certain contribution from basements and basalts. In addition, the in-situ Pb isotopic ratios increase as altitude increases (from 720 to 760 m), which suggests that the migration of metal-bearing fluids is most likely to go upward, and with the evolution of hydrothermal system, the contribution of radiogenic Pb-depleted basements and basalts was declining. This paper proposed that (i) Pb-Zn ores do not select strata, but are selective for lithology, (ii) various processes are responsible for the ore formation at Maoping, including BSR and TSR, fluids mixing and sulfide rapid precipitation, and (iii) the multi-layer metallogenesis of the Maoping carbonated-hosted epigenetic Pb-Zn deposit is a coupling mineralization of ore-forming fluids, trapped structure systems and favorable lithological combinations, which is different from that of typical Mississippi Valley-type (MVT) deposits.