Determining crustal melting in parallel with geodynamic evolution provides critical information on plateau crustal thickening and uplift. Here we investigate the timing and duration of crustal melting through in-situ analysis of zircon U-Pb ages, trace elements and Hf-O isotopes, and whole-rock elements and Sr-Nd-Hf isotopes for the granites and high-grade metamorphic rocks from the Pamir Plateau. Zircon dates record protracted crustal melting for both Central Pamir (43–33 Ma and 22–12 Ma) and South Pamir (28–10 Ma). The Pamir Cenozoic granites are characterized by significant elemental and isotopic heterogeneity. The elemental variability within the Pamir Cenozoic granites is attributed to fractional crystallization of dominantly K-feldspar and plagioclase with subordinate biotite from a variably fractionated melt, and the accumulation of early crystallized feldspar during magma ascent. Peritectic mineral entrainment and accessory mineral crystallization had some influence on the geochemical characteristics of the garnet-bearing leucogranite dikes. Zircon Hf isotopes and whole-rock Sr-Nd-Hf isotopes show secular variations for both Central and South Pamir granites. The Central Pamir granites show a mild decrease in whole-rock ƐNd(t) values from Eocene (-4.3 to -4.9) to Miocene (-6.2 to -7.7), and the zircon ƐHf(t) values decrease from c. 40 Ma (+2 to -5) to c. 10 Ma (-4 to -8). In contrast, the South Pamir granites have highly variable whole-rock Sr-Nd-Hf (87Sr/86Sr(i) = 0.70530 to 0.78302; ƐNd(t) = -31.5 to +0.2; ƐHf(t) = -40.0 to +8.2) and zircon Hf isotopes (ƐHf(t) = +7.5 to -31.7) and displays a strong decrease in ƐNd(t) and ƐHf(t) values from c. 25 Ma to c. 13 Ma. Geochemical and isotopic data indicate that both the Central and South Pamir experienced crustal melting from juvenile lower crust to ancient lower-middle crustal materials, and Indian crustal materials were incorporated into the melt region of the South Pamir leucogranites from c. 20 Ma. Our study highlights a causal link between a chain of events that includes magma underplating induced by lithosphere thinning and slab breakoff, lithosphere delamination and underthrusting of Indian lithosphere, and formation of the Cenozoic granites in Pamir. This series of processes are incorporated here into a comprehensive model for the geodynamic evolution of the Pamir during the India-Asia collision.