Display omitted •First study to assess climate change impacts on water availability in KarMo basin.•Climate projection based on an ensemble of a set of RCMs selected rigorously.•Higher rate of increase in Temperature in mountains and precipitation in dry season.•Climate change impacts on water are larger at higher altitudes than southern plains. Karnali-Mohana river basin, Western Nepal. This study aims to project future climate and assess impacts of climate change (CC) on water availability in the Karnali-Mohana (KarMo) basin. Bias-corrected future climate was projected based on ensembles of multiple models selected from a set of 19 regional climate models (RCMs). The impacts on water availability were then assessed by forcing a well calibrated and validated hydrological model with projected future precipitation (P) and temperature (T) for various climatic scenarios. Results showed that future T is projected to increase spatio-temporally with higher rate for the mountain stations in the winter season; whereas future P has no distinct spatio-temporal trend but increase in dry season precipitation for future periods. The projected changes in P, T and evapotranspiration are expected to alter average annual flow at the outlets of the KarMo and its sub-basins, albeit with varying rate. The simulated results showed higher impacts in water availabilty at higher altitudes, thus indicating higher vulnerability of northern mountainous region to CC than the southern flatlands. Being the first ever study of such nature in the study area, these results will be useful for planning and development of climate-resilient water development projects in the region.