Originating from the southern slope of Himalaya, the Karnali River poses a high flood risk at downstream regions during the monsoon season (June to September). This paper presents comprehensive hazard mapping and risk assessments in the downstream region of the Karnali River basin for different return-period floods, with the aid of the HEC-RAS (Hydrologic Engineering Center's River Analysis System). The assessment was conducted on a ~38 km segment of the Karnali River from Chisapani to the Nepal-India border. To perform hydrodynamic simulations, a long-term time series of instantaneous peak discharge records from the Chisapani gauging station was collected. Flooding conditions representing 2-, 5-, 10-, 50-, 100-, 200-, and 1000-year return periods (YRPs) were determined using Gumbel's distribution. With an estimated peak discharge of up to 29,910 m3/s and the flood depths up to 23 m in the 1000-YRP, the area vulnerable to flooding in the study domain extends into regions on both the east and west banks of the Karnali River. Such flooding in agricultural land poses a high risk to food security, which directly impacts on residents' livelihoods. Furthermore, the simulated flood in 2014 (equivalent to a 100-YRP) showed a high level of impact on physical infrastructure, affecting 51 schools, 14 health facilities, 2 bus-stops, and an airport. A total of 132 km of rural-urban roads and 22 km of highways were inundated during the flood. In summary, this study can support in future planning and decision-making for improved water resources management and development of flood control plans on the southern slope of Himalaya. © 2020 by the authors.