The Caixiashan sediment-hosted Zn-Pb deposit (131 Mt at 3.95% Zn + Pb) is located in the western segment of eastern Tianshan, on the southern margin of the Central Asian Orogenic Belt, Xinjiang, northwest China. Zinc and lead mineralization is mainly hosted in the dolomite marble of the Mesoproterozoic Kawabulake Group. Four stages (I to IV) of hydrothermal activity have been identified, i.e., calcite + dolomite + quartz + pyrite stage I, calcite + dolomite + quartz + spahlerite + pyrrhotite ± arsenopyrite stage II, calcite + dolomite + quartz + galena + pyrite ± chalcopyrite stage III, and late quartz + calcite stage IV. Sphalerite and galena mainly occur in the vein ores of stage II and III. Five types of fluid inclusions are distinguished in the calcite- and quartz-bearing veins, i.e., liquid-rich two-phase (L-type), pure-liquid phase (PL-type), vapor-rich two-phase (V-type), pure-vapor phase (PV-type), and halite-bearing (H-type) inclusions. Fluid inclusions of stages I to IV were homogenized at temperatures of 336–494 °C, 240–357 °C, 140–297 °C, and 71–156 °C, with salinities of 4.0–18.0 wt% NaCl equiv., 4.2–17.3 wt% NaCl equiv., 0.2–13.5 wt% NaCl equiv., and 1.2–7.6 wt% NaCl equiv., respectively. The ore-forming fluids at the Caixiashan deposit are characterized by high- to moderate temperatures, moderate salinities, and low densities, belonging to the H2O–NaCl system. Hydrogen and oxygen isotope data indicate that the ore-forming fluids at Caixiashan have a dominantly metamorphic signature and were diluted by meteoric water. Carbon and oxygen isotope compositions of calcite, dolomite, and marble demonstrate that the ore-forming fluids were primarily sourced from the dissolution and low-temperature alteration of carbonates. Sphalerite, galena, pyrrhotite, and pyrite samples from stage I to III record high δ34SV-CDT values between 11.2 and 16.1‰, indicating a predominant sulfur source from the Precambrian marine sulfates by thermochemical sulfate reduction. The 206Pb/204Pb, 207Pb/204Pb, and 208Pb/204Pb ratios of sulfide samples are similar to those of marble and carbonaceous slate of the Kawabulake Group, whereas they differ from those of granitoid rocks, suggesting that ore-forming metals may have been primarily derived from the Precambrian basement. All of these observations combined with the stable and radiogenic isotope results reveal that the formation of the Caixiashan Zn-Pb deposit was dominated by a metamorphic system, and the ore-forming components were sourced from the Precambrian basement.