Partial melting is thought to profoundly impact the rheology and deformation behavior of the middle crust. Consequently, investigations of the pressure-temperature conditions of metamorphism, rates of heating, and durations of anatexis can provide unique constraints on tectonic processes. The Greater Himalayan Sequence (GHS), in the metamorphic core of the Himalayan orogen, is commonly considered to represent exhumed, anatectic, mid-crust. Here, we present detailed petrological and geochronological analysis of anatectic pelitic schist and felsic paragneiss from the uppermost structural level of the GHS to understand the timing and conditions of Himalayan anatexis. Petrologic analysis indicates that these rocks experienced high-grade metamorphism and partial melting up to peak conditions of ca. 720–745°C and ca. 9.6–10 kbar. Melt volumes of ca. 3% increased slightly during exhumation with nearly constant or slightly decreasing temperature, then decreased as rocks cooled, ultimate crossing the solidus at ca. 5.5 kbar and 700°C. Well-correlated U–Th–Pb ages and trace element data (HREE, Y, and Eu/Eu*) for monazite and zircon require prograde metamorphism and initial partial melting of GHS rocks at ca. 50 and 42–40 Ma, respectively, and crystallization of melts at ca. 24–18 Ma. These data indicate a long-lived (ca. 22–24 Myr) partially molten mid-crust in the eastern Himalayan orogen that formed as much as 10 Myr earlier and lasted 10 Myr longer than numerical models of viscous flow have predicted. Thermal buffering and melt stagnation may reflect feedbacks between thermal structure and shear stress. The change from thermal and mechanical stasis to rapid exhumation and cooling at ca. 24 Ma corresponds with an orogen-wide shift in deformation patterns, and may reflect arrival of mainland India.