The Vietnamese Mekong Delta (VMD) is one of the world’s most vulnerable deltas to climate change and sea level rise. Adequate understandings of future hydrological changes are crucial for effective water management and risk-proofing, however, this knowledge body is currently very limited. This study quantifies the responses of the VMD’s river flow regime to multiple stimuli, namely future upstream inflow variation, local climate change, and sea level rise. The one-dimensional hydrodynamic model MIKE 11 was used to simulate discharges and water levels across the delta. We developed four scenarios to represent changes in the upstream discharges, precipitation changes and sea level rise, covering the 2036–2065 period. We downscaled climate data and applied three bias-correction methods for five General Circulation Models (GCM), and two Representative Concentration Pathways (RCPs). The climate change projections show similar trends of increasing wet season precipitation and decreasing dry season precipitation. However, cross-scenario variations are sometimes large, depending on the individual GCMs, the RCPs and specific locations. The hydraulic simulation results indicate that, under discharge changes between −20% and +10%, combined with in-delta precipitation variations during the dry season, river discharges at the four representative stations could reduce substantially from −2.5% to −100.2%. During the wet season, the calculated river discharges show increase between 7.3% and 46.7% under four considered scenarios. Substantial changes in the VMD’s river flow regime could have potentially serious implications for water management, especially saltwater intrusion, and therefore calling for timely adaptation measures.