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To understand the early topographic growth of the Tibetan Plateau and the causes and effects of climate change in this region, it is important to reconstruct the drainage evolution across Southeast Tibet. Based on age constraints provided by detrital zircons in the fluvial sandstones in the Khorat Plateau Basin, we identified a major Early Cretaceous drainage disruption and reorganization event. The ages and Hf isotope compositions of the detrital zircons in the Upper Jurassic-Lower Cretaceous Phu Kradung to Phu Phan formations (166–122 Ma) suggest the existence of an exorheic continental-scale paleo-Mekong River with headwaters in the Songpan-Garze and Qiangtang terranes. This paleo-river flowed southwards across the Khorat Plateau to what is presently the offshore Phuquoc Basin, which was then part of the Neo-Tethys Ocean. In contrast, the U-Pb-Hf compositions of the detrital zircons in the Lower Cretaceous Khok Kruat Formation (122–113 Ma) indicate that a prominent detrital supply from the Sibumasu magmatic rocks was transported by the paleo-Salween River. This major change reflects the occurrence of ancestral transcontinental river disruption at around 122 Ma, which was driven by the final collision between the Lhasa and Qiangtang and Woyla Arc and Sibumasu terranes. The tectonic uplift and ensuing arid climate corresponded to the reorganization of the ancestral Mekong drainage system during the Mid-Cretaceous (113–94 Ma). [ABSTRACT FROM AUTHOR]