The Main Central Thrust Zone (MCTZ) is a key tectonic feature in the architecture of the Himalayan chain. In the Arun valley of the eastern Nepal Himalaya, the MCTZ is a strongly deformed package of amphibolite- to granulite-facies metapelitic schist and granitic orthogneiss. This package is tectonically interposed between the underlying, low-grade, Lesser Himalaya sequences and the overlying, high-grade and locally anatectic, Higher Himalayan Crystallines (HHC). The MCTZ is characterized by a well documented inverted metamorphism from the Grt–Bt zone, across the Ky-in, St-in and -out, Kfs-in, Ms-out and Sil-in isograds. Partial melting with local occurrence of migmatitic segregations has been rarely reported from the highest structural levels of the MCTZ. While it is widely accepted that thrusting along the MCT occurred during the Miocene, geochronological data constraining the timing of crustal anatexis in the upper portion of the MCTZ are still lacking. In order to understand the link between partial melting in the MCTZ and the Miocene activation of the MCT, we present the P– T–time evolution of a kyanite-bearing anatectic gneiss occurring at the highest structural levels of the MCTZ, along the Arun–Makalu transect (eastern Nepal). Microstructural observations combined with P– T pseudosection analysis show that dehydration partial melting occurred in the kyanite-field. After reaching peak conditions at about 820 °C, 13 kbar, the studied sample experienced decompression accompanied by cooling down to 805 °C, 10 kbar, which caused in situ melt crystallization. SHRIMP monazite and zircon geochronology provides evidence that the anatexis affecting the upper portion of the MCTZ occurred during Early Oligocene (∼ 31 Ma). These results demonstrate that in the upper MCTZ, at least in the eastern Himalaya, crustal anatexis was earlier than, and not a consequence of, decompression linked to exhumation along the MCT.