Determining early orogenic processes within the Pamir-Tibet orogen represents a critical step toward constructing a comprehensive model on the tectonic evolution of the region. Here we investigate the timing and cause of prograde metamorphism of Cenozoic metamorphic rocks from the Pamir plateau through Lu-Hf geochronology, U-Pb rutile thermochronology, and garnet thermometry. Regional prograde metamorphism and heating to 750–830 °C, as constrained by thermometry, occurred between 37 and 27 Ma. Prograde growth of garnet first occurred in the South Pamir and spread to the Central Pamir during the following 10 m.y. The early metamorphism is attributed to high mantle heat flow following the ca. 45 Ma break-off of the Indian slab south of the Pamir. Our investigation confirms a long-lived thermal history of the Pamir deep crust before the Miocene, and provides a causal link between break-off, enhanced mantle heat flow, and prograde heating of the subduction hanging wall.