We investigated a contractional shear zone located in central Nepal, known as Kalopani shear zone. This high-temperature shear zone triggered the early exhumation of the metamorphic core in the Himalayan belt and deeply affected the tectono-metamorphic history of the crystalline rocks soon after the collisional stage. Pseudosection modeling and inverse geothermobarometry reveal that rocks involved in the Kalopani shear zone experienced pressure-temperature conditions between 0.60 and 0.85 GPa and 600 and 660 °C. U-Th-Pb in situ laser ablation-inductively coupled plasma-mass spectrometry and sensitive high-resolution ion microprobe dating on monazite points to retrograde metamorphism related to the Kalopani shear zone starting from ca. 41 to 30 Ma. The kinematics of the Kalopani shear zone and associated erosion and/or tectonics caused the middle-late Eocene exhumation of the Greater Himalayan Sequence in the hanging wall of the Kalopani shear zone at least 9 m.y. before the activities of the middle tectonicmetamorphic discontinuity in the Greater Himalayan Sequence (High Himalayan discontinuity), the Main Central thrust, and the South Tibetan detachment. Structural data, metamorphic conditions, and geochronology from the Kalopani shear zone, compared to those of other major tectonic discontinuities active within the Greater Himalayan Sequence in the Kali Gandaki valley, indicate that shear deformation and exhumation were not synchronous all over the Greater Himalayan Sequence but migrated downward and southward at different lower levels. These processes caused the exhumation of the hanging wall rocks of the activated shear zones. The main consequence is that exhumation has been driven since the middle-late Eocene by an in-sequence shearing mechanism progressively involving new slices of the Indian crust, starting from the metamorphic core of the orogen and later involving the outer portions of the belt. This challenges the common view of exhumation of the Greater Himalayan Sequence mainly driven by the coupled activity of Main Central thrust and South Tibetan detachment between ca. 23 and 17 Ma.