The Mekong Delta has the world’s third-largest surface area. It plays an indisputable role in the economy and livelihoods of Vietnam and Cambodia, with repercussions at regional and global scales. During recent decades, the Vietnamese part of the Mekong Delta underwent profound human interventions (construction of dykes and multi-channel networks), which modified the hydrodynamic regime, especially cycles of field submersion. In this study, we first applied a full 2D numerical hydraulic model, TELEMAC-2D, to examine the effects of the complex channel and river networks on the spatial and temporal distribution of the flow in the 40,000 km² of the Vietnamese Mekong Delta. Then, two scenarios of relative sea-level rise in 2050 and 2100 were implemented to simulate the future patterns of water fluxes in the delta. The results show that dykes and multi-channel networks would reduce the inundation area by 36% and lessen the peak water level by 15% and the discharge over the floodplains by 24%. Despite this protection, under a relative sea-level rise of 30 cm and 100 cm, the maximum flooded area could occupy about 69% and 85% of the whole delta in 2050 and 2100, respectively.