Salinity intrusion in the Vietnamese Mekong Delta (VMD) has been exacerbated significantly in recent years by the changing upstream inflows, sea level rise resulting from climate change, and socioeconomic development activities. Despite significant damage to agricultural production and freshwater supplies, quantitative assessments of future flows and salinization remain limited due to lack of observation data and modelling tools to represent a highly complex hydraulic network. In this study, we combine 1D-MIKE 11 and 2D-MIKE 21 hydrodynamic models to simulate future flows, water level and salinity intrusion in the Hau River—one main river branch in the Mekong Delta. Future hydrological changes are simulated under multiple scenarios of upstream inflow changes, climate change and sea level rise for the 2036–2065 period. We first use the 1D-MIKE 11 to simulate the flow regime throughout the whole VMD using upstream discharges, outlet water levels and rainfall data as boundary conditions. Output from this step is then used to force the 2D-MIKE 21 model to estimate flow velocity, water level and salinity concentration in the Hau River, focusing on the salinization-prone section between Can Tho, Dinh An, and Tran De estuaries. Simulation results show that salinization will increase substantially, characterized by (1) higher salinity intrusion length under spring tide from 6.78% to 7.97%, and 8.62% to 10.89% under neap tide; and (2) progression of the salinity isohalines towards the upper Mekong Delta, from 3.29 km to 3.92 km for 1 practical salinity unit (PSU) under spring tide, and 4.36 km to 4.65 km for 1 PSU concentration under neap tide. Additionally, we found that salinity intrusion will make it more difficult to re-establish the freshwater condition in the estuary in the future. In particular, the flushing time required to replace saltwater with freshwater at the estuaries tends to increase to between 7.27 h for maximum discharge of 4500 m3/s and 58.95 h for discharge of 400 m3/s under the most extreme scenario. Increasing salinization along the Hau River will have important consequences for crop production, freshwater supplies and freshwater ecosystems, therefore requiring timely adaptation responses.