India-Asia collision has resulted in the largest orogenic event on Earth since at least 500 Ma, and this has had a profound influence on the drainage patterns of Asia, on the Asian monsoon climate, on global oceanography, as well as on faunal extinctions. Despite this importance, understanding of the Paleogene evolution of this system is limited. U-Pb and Lu-Hf isotopic analyses of detrital zircons from the clastic sedimentary rocks of the Indus Molasse, located within the Indus Suture of the Ladakh Himalaya, India, show that most have Mesozoic-Cenozoic ages and juvenile Hf isotopic compositions. This suggests that the main source of these sediments is the Transhimalayan batholith, with minor flux from the Lhasa-Karakoram terrane and Indian plate. The lower Indus Molasse (Chogdo Formation) is inferred to have been deposited at 60-49 Ma, whereas the upper Choksti Formation was deposited later than 45-41 Ma and contains a greater contribution from the Lhasa terrane. The Transhimalayan batholith was eroded throughout Indus Molasse sedimentation, but increasing exhumation of Lhasa-Karakoram terrane indicates its progressive uplift after initial collision, and requires formation of a paleo-Indus River shortly after collision.