Abstract: The Ngan Sau River basin, which is situated in Ha Tinh Province of Vietnam, experiences flooding during the rainy season, resulting in significant loss of property and human life. This research aimed to investigate the impact of climate change and land-use variation on flood losses. The study began by simulating the heavy rainfall events in August 2007 using the Weather Research and Forecast model with an ensemble method. Future rainfall was examined through numerical simulation based on pseudo-global warming constructed using six CMIP5 models (MIROC-ESM, MRI-CGM3, GISS-E2-H, HadGEM2-ES, HadGEM2-ES, and CNRM-CM5), and the variation in land-use was obtained from local authorities. Inundations caused by rainfall in 2007 and rainfall in the future were determined by the rainfall-runoff-inundation model. Finally, based on flood maps, land-use, and flood depth-damage functions, the economic losses were computed. The results of the average flood economic loss were $380 million in CTL, whereas the local authorities report an estimated loss of over $300 million. Under the impact of climate change and land-use variation, economic losses ranged from $380 million to $526 million in six CMIP5 models. The result of INMCM4 showed the highest value of $526 million, the results of MRI-CGM3, GISS-E2-H, HadGEM2-ES, and CNRM-CM5 fluctuated around $500 million, and the MIROC-ESM recorded the lowest at $380 million. The damage maps showed that the losses would be highest in urban areas, followed by forest areas, and lowest in agricultural areas. This information is essential for decision-makers to improve solutions for preventing economic losses caused by floods.