The Southern Alps host volcano-sedimentary basins that formed during post-Variscan extension and strike-slip in the Early Permian. We present U-Pb ages and initial Hf isotopic compositions of magmatic zircons from silicic tuffs and pyroclastic flows within these basins, from caldera fillings and from shallow intrusions from a 250 km long E-W transect (Bozen- Lugano-Lago Maggiore) and compare these with previously published data. Basin formation and magmatism are closely related to each other and occurred during a short time span between 285 and 275 Ma. The silicic magmatism is coeval with mafic intrusions of the Ivrea-Verbano Zone and within Austroalpine units. We conclude that deep magma generation, hybridisation and upper crustal emplacement occurred contemporaneously along the entire transect of the Southern Alps. The heat advection in the lower crust by injected mantle melts was sufficient to produce crustal partial melts in lower crustal levels. The resulting granitoid melts intruded into the upper crust or rose to the surface forming large caldera complexes. The compilation of Sr and Nd isotopic data of these rocks demonstrates that the mantle mixing endmember in the melts may not be geochemically enriched but has a depleted composition, comparable to the Adriatic subcontinental mantle exhumed to form the Tethyan sea floor during Mesozoic continental breakup and seafloor spreading. Magmatism and clastic sedimentation in the intracontinental basins was interrupted at 275 Ma for some 10-15 million years, forming a Middle Permian unconformity. This unconformity may have originated during large-scale strike-slip tectonics and erosion that was associated with crustal thinning, upwelling and partial melting of mantle, and advection of melts and heat into the crust. The unconformity indeed corresponds in time to the transition from a Pangea-B plate reconstruction for the Early Permian to the Late Permian Pangea-A plate assembly (Muttoni et al. in Earth Planet Sci Lett 215:379-394, 2003). The magmatic activity would therefore indicate the onset of >2,000 km of strike-slip movement along a continental-scale mega-shear, as their model suggests