The Zhaxikang Pb-Zn-Ag-Sb deposit, the largest polymetallic deposit known in the Himalayan Orogen of southern Tibet, is characterized by vein-type mineralization that hosts multiple mineral assemblages and complicated metal associations. The deposit consists of at least six steeply dipping vein-type orebodies that are hosted by Early Jurassic black carbonaceous slates and are controlled by a Cenozoic N–S-striking normal fault system. This deposit records multiple stages of mineralization that include an early period (A) of massive coarse-grained galena–sphalerite deposition and a later period (B) of Sb-bearing vein-type mineralization. Period A is only associated with galena–sphalerite mineralization, whereas period B can be subdivided into ferrous rhodochrosite–sphalerite–pyrite, quartz–sulfosalt–sphalerite, calcite–pyrite, quartz–stibnite, and quartz-only stages of mineralization. The formation of brecciated galena and sphalerite ores during period A implies reworking of pre-existing Pb–Zn sulfides by Cenozoic tectonic deformation, whereas period B mineralization records extensive open-space filling during ore formation. Fluid inclusion microthermometric data indicate that both periods A and B were associated with low–medium temperature (187–267°C) and low salinity (4.00–10.18% wt. NaCl equivalent) ore-forming fluids, although variations in the physical–chemical nature of the period B fluids suggest that this phase of mineralization was characterized by variable water/rock ratios. Microprobe analyses indicate that Fe concentrations in sphalerite decrease from period A to period B, and can be divided into three groups with FeS concentrations of 8.999–9.577, 7.125–9.109, 5.438–1.460 mol.%. The concentrations of Zn, Sb, Pb, and Ag within orebodies in the study area are normally distributed in both lateral and vertical directions, and Pb, Sb, and/or Ag concentrations are positive correlation within the central part of these orebodies, but negatively correlate in the margins. Sulfide S isotope compositions are highly variable (4‰–13‰), varying from 4‰ to 11‰ in period A and 10‰ to 13‰ in period B. The Pb isotope within these samples is highly radiogenic and defines linear trends in 206Pb/204Pb vs. 207Pb/204Pb and 206Pb/204Pb vs. 208Pb/204Pb diagrams, respectively. The S and Pb isotopic characteristics indicate that the period B orebodies formed by mixing of Pb–Zn sulfides and regional Sb-bearing fluids. These features are indicative of overprinting and remobilization of pre-existing Pb–Zn sulfides by Sb-bearing ore-forming fluids during a post-collisional period of the Himalayan Orogeny. The presence of similar ore types in the north Rhenish Massif that formed after the Variscan Orogeny suggests that Zhaxikang-style mineralization may be present in other orogenic belts, suggesting that this deposit may guide Pb–Zn exploration in these areas.