The Can Tho River plays an important role in ensuring water supply for life and socio-economic activities of Can Tho city. The problem is that the water supply and water demand in the future are difficult to predict. Therefore, it needs an approach which is capable of analyzing the water balance. This study aims to identify the impact of climate change and socio-economic development on the water balance and water quality in the future (2030s and 2050s). We used the Vietnam Water Quality Index (VN-WQI) as an analysis tool and the Water Evaluation and Planning (WEAP) model. Results show that in the period of 2010-2019, both water quality and quantity of the Can Tho River can still meet the water demands. However, the Can Tho River will not be able to use due to pollution of BOD, COD and NH4+-N matters in the future. The water demand increases significantly under the impacts of rapid urbanization and industrialization. Thus, this also increases wastewater discharged into the Can Tho River. The surface water of the Can Tho River is projected to be declined under the impacts of climate change. We found that the water supply is much higher than the water demand in Can Tho city, so the water quality is the deciding factor for different purposes.