The Fuli Pb-Zn deposit is situated at the southwestern margin of the Yangtze Block in Yunnan. The deposit, which is hosted in the Permian Yangxin Formation dolomite, is a recent discovery. Our study indicates a significant presence of fluid inclusions in sphalerite from the Fuli Pb-Zn deposit, with fewer inclusions observed in dolomite and calcite. We conducted comprehensive petrographic, microthermometric, and laser Raman analyses on the inclusions within sphalerite and dolomite. Additionally, six samples of dolomite from the mineralization period were selected for H-O isotope analysis. The results of our study reveal the characteristics of ore-forming fluids and explore the mechanisms of ore formation. The study results indicate that the Fuli Pb-Zn deposit is a low- to medium-temperature hydrothermal deposit with fluid inclusions mainly composed of two-phase gas-liquid inclusions. Salinity and homogenization temperature analyses affirmed that there are two types of fluids present, one with low salinity and the other with high salinity. Laser Raman tests demonstrated the presence of CH4, N2, and CO2 in the gas phase of the inclusions. Microthermometric analyses indicated that the sphalerite ore-forming fluids consist of a multicomponent system of Mg2+ and Ca2+ enriched fluids. The features of the ore-forming fluids in the Fuli deposit arise from a blend of high-temperature, low-salinity metamorphic fluids and low-temperature, high-salinity basin brines. The basin brines in question have the potential to emanate from the Youjiang Basin. The formation of the ore is ascribed to the TSR and the mixing of fluids. The combination of these processes provided the requisite materials (SO42−), catalysts (Mg2+), and reducing agents (organic matter, CH4, and H2S) required to initiate the thermochemical sulfate reduction (TSR). As the TSR proceeded, it caused a shift in the pH of the fluids, thus promoting the precipitation of metal sulfides.