Determining the association of Pb–Zn(-Ag) mineralization with granite is crucial for understanding metallogeny and identifying exploration targets. The genesis of Pb–Zn-Ag-Sb deposits and their genetic association with Sb(-Au) deposits and granite-associated Sn-W deposits in the Tethys Himalaya of southern Tibet, China, remains controversial. Our comprehensive study of in situ element compositions and sulfur isotopes of sulfides, together with in situ quartz oxygen isotopes for the Zhaxikang Pb–Zn-Ag-Sb deposit, sheds light on this issue. LA-ICP-MS analyses of early sulfides in manganosiderite veins, coupled with C-O isotopes of manganosiderite, indicate that the early fluids were enriched in Pb, Zn, Ag, Sb, Sn, and Cu, originating from magmatic fluids mixing with meteoric water. The early formed sulfides underwent fluid-mediated remobilization and dissolution, releasing many metallic elements (e.g., Pb, Zn, and Ag) into later As-Sb-rich fluids. These elements reprecipitated as Fe-poor sphalerite, As-rich pyrite, and abundant Sb-Pb sulfosalts with minor Ag-bearing minerals. Oxygen isotopes of quartz indicate that the later fluids were derived from pulsed releases of magmatic fluids mixing with meteoric water. In situ sulfur isotopes of three generations of pyrite indicate that early Pb–Zn(-Ag) sulfide precipitation was linked to magmatic sulfur, whereas precipitation of the later sulfosalts and stibnite involved external sulfur with relatively lower sulfur isotopes compared with early mineralization. We argue that Pb–Zn-Ag-Sb deposits in the Tethys Himalaya resulted from two distinct mineralization pulses. The early Pb–Zn(-Ag) mineralization was associated with crustal magmatic rocks (e.g., leucogranite), followed by the overprinting of later Sb-rich magmatic fluids. Notably, the later magmatic fluids responsible for Zhaxikang Pb–Zn-Ag-Sb mineralization were also associated with the regional Sb(-Au) deposits in the Tethys Himalaya.