Effective water management plays an important role in socioeconomic development in the Vietnamese Mekong Delta (VMD). The impacts of climate change and human activities (that is, domestic consumption and industrial and agricultural activities) vary in different subregions of the delta. In order to provide intersectoral data for determining the significantly impacted subregions of the VMD, the present study simulated interactions between local climatic patterns, human activities, and water resources using a system dynamics modeling (SDM) approach with each subregion as an agent of the developed model. The average rainfall and temperature of 121 subregions in the VMD were collected during 1982–2012, and the future changes of climate by provinces were based on the Representative Concentration Pathways (RCP) scenarios (RCP4.5 and RCP8.5) by the end of 21st century. The assessment was based on the levels of impact of various factors, including (1) water consumption, (2) differences between evapotranspiration and rainfall, and (3) spatial distribution of salinity intrusion over the delta scale. In the coastal areas, as well as the central and upstream areas, water resources were projected to be affected by environmental changes, whereas the former, characterized by the lack of surface freshwater, would be affected at a greater scale during the dry season. Besides, the sea level rise would lead to an increase in negative impacts in the eastern coastal areas, suggesting that water-saving techniques should be applied not only for agriculture, but also for industry and domestic water consumption during the dry season. In addition, the south subregions (that is, the western subregions of the Hau River except for An Giang) were likely to be flooded due to the simulated high rainfall and seasonal rises of sea level during the wet season. Therefore, the alternative forms of settlement and livelihood should be considered toward balance management with changing delta dynamics.