The Kargah Cu-Pb polymetallic deposit is a newly discovered ore deposit from the Gilgit-Baltistan region, located in the Kohistan Island Arc, northern Pakistan. However, this area is poorly researched on the ore genesis, and its origin and the evolution of its magmatic-hydrothermal system remain unclear. Three stages of mineralization were identified, including quartz-pyrite, quartz-sulfide, and carbonate representing early, middle, and late stages, respectively. The major ore minerals are pyrite, chalcopyrite, galena, and zincian tetrahedrite with minor native silver, and native gold mainly distributed in pyrite. Here, we present a systematic study on ore geology, hydrothermal alterations, trace element composition of pyrite, fluid inclusions, and isotopes (S and Pb) characteristics to gain insights into the nature of the ore-forming fluids, types of unknown deposits, and hydrothermal fluid evolution. The high Co/Ni ratio (1.3–16.4) and Co content (average 1201 ppm), the low Mo/Ni ratio (0.43–0.94) and Mo contents (average 108 ppm) of both Py-I and Py-II suggest a mafic source for the mineralization. The Au-Ni plots, Co-As-Ni correlation, and the δ³⁴S values range from −2.8 to 6.4‰ (average of 3.4‰) indicating the affiliation of the mineralization with a mantle-derived magmatic-hydrothermal provenance. The Pb isotope data showing the narrow variations in ²⁰⁶Pb/²⁰⁴Pb, ²⁰⁷Pb/²⁰⁴Pb and ²⁰⁸Pb/²⁰⁴Pb values suggest a single lead source from crustal-derived materials. The microthermometry data suggest that the dominant mechanisms are fluid boiling and mixing for mineral precipitation at temperatures ranging between 155 and 555 °C, and represent an intrusion-related magmatic-hydrothermal environment for the Kargah Cu-Pb polymetallic deposit.