The Aerhada Pb–Zn–Ag deposit is on the western margin of the Great Xing’an Range in NE China. Prior studies on this deposit lack information regarding precise mineralization age and convincing genetic interpretation, which limits both the prospecting at Aerhada and the reconstruction of the regional metallogenic evolution. Based on a detailed field investigation and microscopic observation, in this study, our aim was to determine the origin and evolution of the hydrothermal system and the timing of magmatism and mineralization, as well as to develop a possible metallogenic model, by revealing information regarding the mineralization paragenetic relationship, fluid inclusions, H–O–C–S–Pb isotopes, and sphalerite Rb–Sr and zircon U–Pb ages. Three successive mineralization stages were recognized: stage I quartz-arsenopyrite-pyrite, stage II quartz-sphalerite-galena, and stage III fluorite-calcite-pyrite. Four types of fluid inclusions were also identified in host minerals: CH4-rich two-phase, halite-bearing, vapor-rich two-phase, and liquid-rich two-phase. Fluid inclusion and microthermometric results showed that the homogenization temperatures were 287–341 °C for stage I, 237–291 °C for stage II, and 162–230 °C for stage III, with respective salinities of 1.7–40.2 wt%, 6.7–10.9 wt%, and 4.2–8.8 wt% NaCl equivalent. The δ18Ofluid and δDfluid values of quartz in stage I (δ18Ofluid = 8.6–10.3 ‰, δDfluid = -126.6 to −124.3 ‰) indicated that initial magmatic water interacted with organic strata, while decreasing the values of quartz in stage II (δ18Ofluid = 3.9–6.8 ‰, δDfluid = -129.1 to −127.6 ‰) and calcite in stage III (δ18Ofluid = -3.5 to −1.0 ‰, δDfluid = -115.5 to −113.4 ‰), showing a trend of dilution and cooling by meteoric water. The negative δCfluid values (δCfluid = -15.9 to −12.6 ‰) of quartz fluid inclusions from stages I and II emphasize that organic carbon was added to the hydrothermal system through water–rock interactions. The δ34S values (δ34Ssulfides = 1.2–7.5 ‰) and lead isotope data of sulfides (206Pb/204Pb = 18.153–18.684, 207Pb/204Pb = 15.370–15.750, 208Pb/204Pb = 37.653–39.301), coupled with those of the hidden biotite granite and Devonian strata, indicate that the ore-forming material was primarily derived from magma and wall rocks. The sphalerite samples produced a Rb–Sr isochron age of 154.1 ± 3.5 Ma (2σ, MSWD = 0.82, n = 8), which was like the zircon U–Pb age of biotite granite (156.3 ± 1.4 Ma, 2σ, MSWD = 0.89, n = 14). Combining the alteration pattern, fluid inclusions, and isotopic and geochronological studies, it was concluded that Aerhada is a magma-related hydrothermal Pb–Zn deposit formed under the post-collision extension setting following the Mongol–Okhotsk Ocean closure during the Late Jurassic period. The proposed metallogenic model is expected to assist in the exploration and development of polymetallic mineralization in the Great Xing’an Range.