Zircons and monazites from 6 samples of the North Ayilari dextral shear zone (NAsz), part of the Karakorum fault zone (KFZ), have been dated with the U-Th-Pb method, using both ID-TIMS and SIMS techniques. The ages reveal (1) inheritance from several events spanning a long period between the late Archean and the Jurassic; (2) an Eocene-Oligocene magmatic event (∼35–32 Ma); (3) an Oligo-Miocene magmatic event (∼25–22 Ma), at least partly synkinematic to the right-lateral deformation; and (4) a period of metamorphism metasomatism (∼22–14 Ma) interpreted as thermal and fluid advection in the shear zone. The Labhar Kangri granite located ∼375 km farther Southeast along the KFZ is dated at 21.1 ± 0.3 Ma. Such occurrence of several Oligo-Miocene granites along the KFZ, some of which show evidence for synkinematic emplacement, suggests that the fault zone played an important role in the genesis and /or collection of crustal melts. We discuss several scenarios for the onset and propagation of the KFZ, and offset estimates based on the main sutures zones. Our preferred scenario is an Oligo-Miocene initiation of the fault close to the NA range, and propagation along most of its length prior to ∼19 Ma. In its southern half, the averaged long-term fault-rate of the KFZ is greater than 8 to 10 mm/a, in good agreement with some shorter-term estimates based on the Indus river course, or Quaternary moraines and geodesy. Our results show the KFZ cannot be considered as a small transient fault but played a major role in the collision history.