The medium-sized Lianhuashan Cu sulfide deposit is located in the southern Xing’an Range of Inner Mongolia, NE China. The zoned massive sulfide vein ores are hosted mainly in the Permian Dashizhai Formation, and the ore veins are controlled by NW–NNW-trending structures. The ore-forming process comprises four stages: arsenopyrite–quartz (I); chalcopyrite–pyrite–quartz (II); pyrite–chalcopyrite–sphalerite–galena–quartz (III); and ore-barren sulfide–quartz–carbonate (IV). Three types of fluid inclusions (FIs), namely vapor-rich two-phase (LV-type), liquid-rich two-phase (VL-type), and daughter mineral-bearing three-phase (SL-type), are distinguished. Stage I, II and III contain all types of FIs (LV-, VL-, and SL-type), with homogenization temperatures (Th) of 268–462°C, 230–382°C and 180–340°C and salinities of 3.4–52.3, 3.4–44.5 and 3.7–39.9 wt% NaCl eqv., respectively, whereas stage IV has only VL-type FIs, with Th = 152–232°C and salinity = 3.4–7.9 wt%. Fluid geochemical data show that the Lianhuashan ore fluids were of medium–high temperature (236–382 °C), high-salinity (31.5–44.5 wt%), and relatively oxidizing conditions, typical of a NaCl-H2O system. The microthermometric and H–O isotope data (δ18OH2O = − 9.0 to 6.1 ‰; δD = − 149.0 to − 99.0 ‰) indicate that the ore fluids were initially magmatic with later meteoric water incursion. The sulfide S (δ34S = − 2.9–3.8 ‰) and Pb (206Pb/204Pb = 17.954 − 18.492, 207Pb/204Pb = 15.427 − 15.739, 208Pb/ 204Pb = 37.815 − 38.357) isotopes support that the metals were magmatic-derived. Fluid boiling, cooling, and meteoric water mixing were likely the main ore precipitation mechanism at Lianhuashan.We suggest that Cu minerals at Lianhuashan were precipitated with boiling at ∼ 1km depth. For the ore-forming granodiorite porphyry (zircon U-Pb age: 252.8 ± 1.8 Ma), geochemical data indicate that the primary magma was formed by partial melting of the thickened or delaminated lower crust. Integrating the available age, geological, and geochemical evidence, we suggest that mineralization at Lianhuashan is spatial–temporal and genetically associated with the granodiorite porphyry, and was formed in a volcanic arc setting after the Paleo-Asian Ocean closure.