Here we report the first investigation of spinel-bearing mantle xenoliths from Los Gemelos volcano, Canquel Plateau, Patagonia. They are highly-depleted Mesoproterozoic (ReOs model ages of 1.3–0.9 Ga) harzburgites and clinopyroxene-poor lherzolites characterized by typical indicators of partial melt extraction, such as low whole-rock Al2O3 and CaO contents (<1.5 wt%), high Mg# of silicate phases (90–95), and Cr-rich spinel (Cr# 0.20–0.42). Depletion of incompatible highly siderophile elements (Re, Ru, Pd) relative to the primitive upper mantle supports high degrees of melt extraction. The occurrence of phlogopite and K-rich alkaline glass veins with high- and low-SiO2 compositions is clear evidence of modal metasomatism. The light rare earth element (LREE) enrichment in clinopyroxene, as well as the whole-rock U-shaped REE pattern, confirms cryptic metasomatism. This melt-rock interaction is corroborated by major (i.e., Mg# vs. basaltic elements) and trace (i.e., La/YbN vs. Sr/Y and Ti/Eu; and Sr vs. Ti/Eu) element contents of pyroxenes. The calculated compositions of melts in equilibrium with clinopyroxene coexisting with phlogopite suggest interaction with slab-derived materials. This metasomatism has been generated by a chromatographic fractionation-reaction process, from deep to shallow mantle domains. The percolation of a high-K hydrous magma probably is associated with the upwelling of asthenospheric material through a slab-window, which caused partial melting of oceanic crust and overlying sediments during the Paleocene. The varying intensities of metasomatic imprints recorded by mantle xenoliths from Los Gemelos provide valuable insights into the interaction of slab-derived materials near the lithosphere-asthenosphere boundary, at a distance of ∼600 km from the Andean volcanic arc.