Convergent margins are commonly deemed to have poor potential to form giant magmatic Ni-Cu-(platinum group element) sulfide deposits, due to the possibly low lithospheric geothermal gradient and the small basaltic magma fluxes. This view, however, is challenged by the recent discovery of the Xiarihamu Ni-Co deposit in the East Kunlun orogen (northern Tibetan Plateau), which contains ~157 million metric tons (Mt) of sulfide ores at 0.65% Ni, 0.013% Co, and 0.14% Cu, making it the world’s 20th largest magmatic sulfide deposit. To investigate the mantle source nature, magmatic processes, and their genetic linkage to Ni-Co mineralization in orogenic belts, we presented new in situ orthopyroxene oxygen isotope and pyroxene trace element data from the mafic-ultramafic cumulate rocks at Xiarihamu. Our results show that orthopyroxene crystals have much higher δ18O (6.40–8.58‰) than those in unmodified mantle peridotite (5.72 ± 0.14‰). Orthopyroxene grains in the primitive harzburgite cumulates have the lowest δ18O values (6.40–7.71‰) and the highest Mg# contents (88.7–83.9). From the harzburgite to the evolved lithologies (e.g., websterite and gabbronorite), the δ18O values of orthopyroxene increase, whereas the Mg# values, Ni contents, and heavy/light rare earth element (HREE/LREE) ratios of orthopyroxene decrease, implying crustal contamination during magma fractionation. The δ18O variations and sharp increases in V/Sc and LREE/HREE ratios from the primitive orthopyroxene crystals (with the highest Ni and Mg#) to the evolved ones (with low Ni and Mg#) indicate that crustal contamination played a critical role in sulfide saturation. The absences of any trend in orthopyroxene δ18O values versus Mg# contents, Ni concentrations, and La/Yb ratios toward unmodified mantle values suggest an enriched mantle source. On the mid-ocean ridge basalt (pyroxene)-normalized multielement plots, both orthopyroxene, clinopyroxene, and calculated parental magma show LREE and large ion lithophile element (LILE) enrichments and depletions in Nb-(Ta), Sr, and Zr-(Hf). The predicted primitive magma trace element compositions and the high-δ18O characteristics of the high-Mg# orthopyroxene grains suggest that the Xiarihamu primitive magma was partly originated from the pyroxenite mantle metasomatized by subducted slab-derived melts and fluids. Given the lower solidus temperature of clinopyroxene relative to olivine, pyroxenites in the mantle wedge may generate voluminous high-Ni magmas during partial melting. The high-Ni magmas are likely conducive to magmatic Ni-Cu sulfide mineralization in orogenic belts.