Crustal melting and granitic intrusions are characteristics of many continental collision zones. The processes, sources and timing of melt generation in collision zones are critical to understanding crustal and tectonic evolution. In the Himalaya, multiple Oligocene-Miocene leucogranite bodies intrude the Greater Himalayan Series (GHS), a lithotectonic package of high-grade metamorphosed sediments. This package is underthrust by a chemically distinct metasedimentary package, the Lesser Himalayan Series (LHS). Multiple elemental and isotopic techniques provide insight into leucogranite source and petrogenesis in central Bhutan (eastern Himalaya). Whole-rock major and trace elemental abundances confirm that all studied leucogranites are the product of muscovite breakdown between 640 and 760°C. Sr-Nd signatures suggest that most samples were sourced from the GHS; however several samples yield signatures more comparable with those from the LHS, an observation that currently appears unique to Bhutan. O, U-Pb, Hf isotopes in zircon confirm previous whole-rock findings that melting in the eastern Himalaya took place over 20 Myr, from 31 to 11 Ma. Increasingly radiogenic Nd and Hf isotope signatures are observed in younger leucogranites, which suggest a deeper source, and potentially more contribution from melting LHS. Importantly, O-Hf isotopic signatures indicate that there is no mantle input into eastern Himalayan melting, a finding important for heat budget calculations and for crustal growth models in orogenic belts. Stable Rb and Sr isotopic analyses from both whole-rock leucogranites and mineral separates establish, for the first time, that mass-dependent isotopic fractionation occurs during the formation of highly evolved crustal melts. Consistent Sr fractionation of up to 2.51‰ is observed between plagioclase, K-feldspar and micas. These observations have implications for the application of stable isotopes as petrogenetic indicators and for Rb-Sr geochronology. Together, the findings of this study provide new insights into both Himalayan and global tectonic evolution and the geochemical nature of melt generation.