The Mazraeh Cu skarn deposit, NW Iran, is situated at the lithological contact between an Oligo−Miocene granodiorite and Cretaceous limestones. The causative granodiorite has I-type medium- to high-K calc-alkaline composition that formed in a subduction arc setting. Metasomatism generated exoskarn and endoskarn characterized by a temporal and spatial mineral-chemistry zonation with massive garnet and garnet-pyroxene proximal and epidote-amphibole skarn at the distal zones of the exoskarn. Our data reveal a multi-stage evolution of the hydrothermal system. Accordingly, the prograde stage was formed by barren, oxidized, high-temperature and hypersaline magmatic fluids, which suggests that the parental magma was emplaced at low lithostatic pressure conditions (∼1.5 km depth). By contrast, during the retrograde stage the regime changed from lithostatic to hydrostatic conditions, resulting in a significant decrease in pressure and oxygen fugacity, boiling, cooling, and mixing, respectively. Dilution by meteoric fluids led to additional cooling and lower salinity of the ore fluids. Sulfur isotope compositions (δ34S = −2.8‰−1.3‰) of sulfides indicate a unique magmatic source of the sulfur. The δ18Ofluid and δDfluid values of the prograde stage fluid also indicate a magmatic origin, while their gradual depletions from the prograde to retrograde stage imply increased mixing with meteoric water. We propose that the fluid mixing scenario continued over the entire life cycle of the mineral system in an open hydrostatic regime as reflected in the oxygen isotope values. It is suggested that boiling and fluid mixing played a significant role in the formation of this giant Cu skarn deposit.