Failure of natural dams on major rivers has caused some of the most destructive freshwater floods on Earth and other planets. Previous studies have identified two Holocene outburst floods in the middle reaches of the Yarlung Tsangpo, along with upstream lacustrine deposits, termed Zangga dammed lake in this study, but it has not been possible to disentangle their causal relationship due to the lack of a robust chronology. The sedimentological similarity between lacustrine deposits of river blockage and aeolian loess formed from proximal materials in the heavily braided river, make it very challenging to re-establish the evolution of dammed lake. This study aims to clarify the origin of megafloods in the middle reach of the Yarlung Tsangpo River by establishing a chronology for Zangga dammed lake based on 12 robust optically stimulated luminescence (OSL) ages from well-defined lacustrine, loess and aeolian deposits. Our results provide hard evidence for repeated river blocking and dam failure events in the middle reach of the Yarlung Tsangpo River, which corresponds well with downstream two megaflood events. Continuous clay varve accumulation indicated that the Zangga dammed lake grew back during 7.5-4.6 ka and generally stable and has persisted at least 3 ka. It is speculated that Zangga dammed lake collapsed during the late Holocene altithermal period, leading to catastrophic outburst flood events in the Yarlung Tsangpo. The age of 7.5-4.6 ka for lake formation means a glacier/moraine mechanism of river blocking is unlikely, as their extent was much reduced, instead landslides were the major blocking agent. Our study provides crucial insights into the complex chronology of dammed-lake events in the middle reach of the Yarlung Tsangpo. Identification of lacustrine sediments, along with OSL dating, has allowed for a more accurate reconstruction of lake evolution. Understanding these dynamics is vital for assessing the potential risks associated with future dammed-lake collapses and their consequential megafloods.