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This study aims to evaluate the impacts of climate change on water balance components, mainly precipitation, water yield, and evapotranspiration and hydrological extremes in three physiographic regions namely the Middle Mountain region, the High Mountain region, and the High Himalayas region of the West Seti River Basin (WSRB) in Nepal. The future climate was projected using the climate data of three Regional Climate Models (RCMs). The projected future climate data was then fed into the hydrological model, Soil and Water Assessment Tool (SWAT), to simulate hydrologic responses including water balance components under future climate conditions. Results showed that the Middle Mountain region of the basin is expected to receive the highest increase of in precipitation (11.2%) and in water yield (18.2%) as compared to the other two physiographic regions. Conversely, the High Himalayas are expected to have the highest increase of evapotranspiration (19.9%) as compared to the Middle Mountain and High Mountain regions. Similarly, the low flows in the basin are expected to decrease by −15.5% and −19.3% under Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios, respectively. Whereas high flows are expected to increase by 10.7% under both the RCP scenarios. The results of this study will be helpful to planners and decision makers to formulate adaptation strategies in water resources development and planning such as irrigation and hydropower development.