The estuaries and coastal zones of the Vietnamese Mekong Delta located at the end of the Mekong Basin are susceptible to a large variety of natural threats and human interventions such as upstream dam construction, climate change and sea level rise. In this study, we investigated sediment dynamics and morphodynamic changes in the Mekong estuaries and coastal zone, using a well-calibrated Delft3D-4 model for a 10-years period simulation. For the first time, the impacts of different drivers were distinguished to guide future adaptation strategies and policies. Our investigations pointed out that the influences of upstream sediment reduction and large-scale sand extraction would cause substantial modifications in the subaqueous delta region. Besides human-induced impacts, modeling results also showed that the sediment volume and spatial distribution changed through the simulated period according to monsoonal variation. The influence of each driver, however, not only varied in space but also time. In the flood season, the Mekong and Bassac Rivers provided a large amount of sediment (more than 90%) that was deposited on the delta front due to coastal processes. The sediment quantity transported along the coastline changed with the monsoon and was in a dominantly south-west direction due to the northeast monsoon, especially in November, December and January. As a natural process, in the estuarine region, erosion and deposition occurred alternately, but the south-west coast region (belonging to the Ca Mau peninsula) was dominated by erosion. This is because of the formation of sand bars in front of the Bassac estuaries, which influences the capacity of sediment transportation to the south-west. Consequently, navigation capacity will reduce significantly in the estuaries and coastline erosion in the Ca Mau peninsula leads to substantial loss of houses and assets of local people. Urgent actions such as stopping sand mining or modifying dam designs are needed to sustain the delta coastline.