Large-scale N-S shortening induced by India-Asia convergence caused the formation of numerous E-W−trending mountain ranges in Tibet. However, the mechanism(s) of formation of N-S−trending mountain ranges remains elusive. We report on a felsic magmatic belt located along the N-S−trending Yardoi-Kongbugang mountain ranges on the flank of the Cona rift in the eastern Tethyan Himalaya. Zircon and monazite geochronology and whole-rock geochemistry revealed three epochs of middle- to lower-crustal anatexis beneath the Cona rift at ca. 47−42 Ma, 35−34 Ma, and 24−14 Ma. The mid-Eocene and early Oligocene granitoids show adakitic signatures indicating continuous crustal thickening, while the formation of Miocene leucogranites and N-S−trending dacitic dikes was related to ductile crustal extension. Silicic melts were exposed along the whole rift since the early Oligocene, suggesting that the early Oligocene could be regarded as a transitional epoch from tectonic compression to orogen-parallel extension. Widespread mid-Eocene and Miocene magmatism in the Himalaya, together with coeval metamorphic anatexis, represents two phases of crustal weakening. The weakened crustal zones under continued India-Asia convergence may have favored uplift and subsequent lateral flow of the weak zones, which initiated E-W extension. Finally, significant upwelling of the weak zones evolved into magma extrusion and formed the N-S−trending mountain ranges. This study provides new insights into the mechanisms of surface uplift and E-W extension and challenges the common view of initiation of E-W extension in southern Tibet not earlier than the early Miocene.