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The Karakoram Fault Zone displays distinctive topographic and tectonic characteristics, with intricate river drainage systems. Although there are extensive thermochronological datasets for the western Tibetan Plateau, limited investigations have been carried out to uncover the low-temperature thermal history of the Karakoram Fault Zone, which connects the Lhasa terrane with the Pamir. In this contribution, apatite fission track (AFT) thermochronology was conducted on 13 basement and 4 conglomerate samples collected from the western Gangdese batholith and the Ayi Mountain Range, on either side of the Karakoram fault. Inverse thermal history modeling results reveal that the western Gangdese batholith experienced two stages of rapid basement cooling at 27–23 Ma (late Oligocene-early Miocene) and 16–4 Ma (middle Miocene-Pliocene). The adjacent Ayi Mountain Range experienced cooling in the late Miocene (∼8 Ma) and during the Pliocene to Pleistocene (4–1 Ma). We suggest that tectonic forces associated with rollback and lateral break-off of the Indian continental lithosphere, and the dextral strike-slip activity of the Karakoram fault were responsible for the first cooling phase. The second accelerated cooling phase was due to the deep fragmentation of the Indian slab, the activity of the Karakoram normal fault, and associated ∼ E -W extension. Additionally, since the late Oligocene, the Indus River incision has likely also contributed to the exhumation of the western Tibetan Plateau. Subsequently, the western Gangdese batholith reached high elevations, resulting in the reversal of the Yarlung River. The dextral-normal motion of the Karakoram fault, which is still active today, was the main cause of the Pliocene to Pleistocene accelerated cooling detected in the Ayi Mountain Range. • Two stages of late Cenozoic rapid cooling occurred in the north of the Karakoram Fault. • The south side of the Karakoram fault experienced Pliocene-Pleistocene rapid cooling. • A topographic inversion occurred in the Karakoram Fault Zone since the early Miocene. [ABSTRACT FROM AUTHOR]