Abstract The Meseta del Lago Buenos Aires (MLBA) in southern Patagonia, a volcanic plateau formed from ~12 Ma to present, provides an opportunity to investigate the temporal evolution in volcanism as this region transitions from the subduction of the Nazca plate to the formation of the slab window produced by the collision of the Chile Ridge and the Andean subduction zone. Here, we report new major, minor, and trace element contents, as well as Sr, Nd, Pb, and Hf isotopes of the MLBA lavas. Three distinct geochemical endmembers can be distinguished in the MLBA basalts: a subduction-influenced endmember, a transitional component similar to the South Atlantic enriched mid-ocean ridge basalts, and an enriched component akin to the EM1 mantle composition. Lavas older than ~1.5 Ma define a compositional continuum between the subduction-influenced and transitional endmembers; this trend is also present in many other southern Patagonian plateaus regardless of their distance to the trench, eruption age, and the composition of the continental blocks where they are located. In contrast, MLBA basalts younger than ~1.5 Ma uniquely define a transition into the EM1 mantle component at the time when this region was affected by the slab window. The estimated pressures and temperatures of mantle-melt equilibration for the MLBA basalts indicates an increase in both parameters after the formation of the slab window that roughly correlate with the changes in lava composition. The basalts’ composition from all southern Patagonia plateaus points to the presence of the South Atlantic mid-ocean ridge basalt mantle influenced by the Discovery, Shona, and Bouvet hotspots rather than the sub-slab mantle, as represented by the Chile Ridge basalts. This observation challenges the hypothesis that the sub-slab mantle within the slab window has had an important role in the composition of the erupted lavas. Instead, it suggests the presence of a South Atlantic mantle beneath southern Patagonia either within the mantle wedge, consistent with a long-lasting South Atlantic convection cell beneath South America, or in the subcontinental lithospheric mantle metasomatized before or just after the opening of the South Atlantic basin, as demonstrated by the composition of southern Patagonia mantle xenoliths. Although it is difficult to precisely distinguish the contributions of the asthenosphere from that of the metasomatized subcontinental lithospheric mantle beneath this region, our work suggests significant contributions from the latter in the composition of the MLBA lavas.