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The Indus River, originating from Manasarovar Lake in Tibet, runs along the Indus Tsangpo suture zone in Ladakh which separates the Tethyan Himalaya in the south from the Karakoram zone to the north. Due to the barriers created by the Pir-Panjal ranges and the High Himalaya, Ladakh is located in a rain shadow zone of the Indian summer monsoon (ISM) making it a high-altitude desert. Occasional catastrophic hydrological events are known to endanger lives and properties of people residing there. Evidence of such events in the recent geologic past that are larger in magnitude than modern occurrences is preserved along the channels. Detailed investigation of these archives is imperative to expand our knowledge of extreme floods that rarely occur on the human timescale. Understanding the frequency, distribution, and forcing mechanisms of past extreme floods of this region is crucial to examine whether the causal agents are regional, global, or both on long timescales. We studied the Holocene extreme flood history of the Upper Indus catchment in Ladakh using slackwater deposits (SWDs) preserved along the Indus and Zanskar Rivers. SWDs here are composed of stacks of sand-silt couplets deposited rapidly during large flooding events in areas where a sharp reduction of flow velocity is caused by local geomorphic conditions. Each couplet represents a flood, the age of which is constrained using optically stimulated luminescence for sand and accelerator mass spectrometry and liquid scintillation counter 14C for charcoal specks from hearths. The study suggests occurrence of large floods during phases of strengthened ISM when the monsoon penetrated into arid Ladakh. Comparison with flood records of rivers draining other regions of the Himalaya and those influenced by the East Asian summer monsoon (EASM) indicates asynchronicity with the Western Himalaya that confirms the existing anti-phase relationship of the ISM-EASM that occurred in the Holocene. Detrital zircon provenance analysis indicates that sediment transportation along the Zanskar River is more efficient than the main Indus channel during extreme floods. Post−Last Glacial Maximum human migration, during warm and wet climatic conditions, into the arid upper Indus catchment is revealed from hearths found within the SWDs.