The Xing'an-Mongolian orogenic belt is an important Ag-Pb-Zn metallogenic province in China. The study on the genesis of the newly discovered Cuiluan hydrothermal vein-type Ag-Pb-Zn deposit located in the Lesser Xing'an Range, within the eastern of Xing'an-Mongolian orogenic belt, is pivotal in understanding the metallogenic mechanism and regularity of Ag-Pb-Zn deposits in this region. This study utilizes pyrite trace elements and sulfur isotopic geochemistry, and mercury isotope of rocks and ores to constrain the genesis of the Cuiluan deposit. Pyrite geochemical data show that Ag exists in the form of galena inclusions (Ag
++(Bi
3+, Sb
3+) ↔ Pb
2+) in the polymetallic sulfide stage, and independent Ag-bearing minerals (matildite and gustavite) precipitate during the main mineralization stage. The small varied δ
34S values (3.24 - 4.94‰) of pyrites from four hydrothermal stages are within the range of magmatic S isotopes, indicating that the ore-forming fluid of the Cuiluan deposit mainly originated from the magma. The Δ
199Hg values of the ores are close to 0‰, which are consistent with the Δ
199Hg values of mantle, further indicating that the ore-forming materials came from the lithospheric mantle. Combined with the regional tectonic evolution, we conclude that the plate subduction of Paleo-oceans in NE China triggered the partial melting of metasomatized mantle. The mantle-derived magma rose along the deep fractures and evolved ore-forming fluids, and finally caused the formation of Cuiluan quartz vein-type Ag-Pb-Zn deposit in the shallow crust. Accompany with previous documents, we infer that the fractures in the large-scale “Granite Sea” in the Lesser Xing'an Range may have significant potential for vein-type Ag-Pb-Zn exploration.