This geochemical, geochronological, and structural study of intrusive rocks in the Sakya dome of southern Tibet has identified two distinct suites of anatectic granites that carry contrasting implications for the tectonic evolution of the India-Asia collision zone. The northern margin of the dome core was intruded by anastomosing, equigranular two-mica garnet granites between 28.1 ± 0.4 Ma and 22.6 ± 0.4 Ma, coeval with top-to-the-south shear. Trace-element and isotopic (Sr-Nd) characteristics indicate an origin from partial melting of a biotite-bearing source in the Indian crust under conditions of high-fluid-phase activity. These granites thus provide evidence for the melt weakening required by some thermo-mechanical models that predict the southward extrusion of a low-viscosity channel during the Oligocene. Evidence for subsequent shear-sense reversal may document initiation of this process. However, a younger suite of porphyritic two-mica granite plutons, emplaced between 14.5 ± 0.9 Ma and 8.81 ± 0.22 Ma, is derived from anatexis of muscovite-bearing metasediments of the High Himalayan Series under fluid-absent conditions. Ar-Ar cooling ages of 14.4–8.0 Ma from the Sakya dome postdate crystallization of the Oligocene granite suite by ∼10 m.y. but are coincident with mid-Miocene granite emplacement, suggesting uplift to depths of <10 km by the mid-Miocene. We propose that plate flexural response to Miocene slab steepening was a likely cause of dome uplift, and that this exhumation of midcrustal rocks triggered decompression melting at 15–9 Ma and emplacement of discrete granite plutons into the upper crust under brittle conditions.