The Mekong floodplains, which encompasses the region from Kratie Township in Central Cambodia to the Vietnamese East Sea, is a region of globally renown agricultural productivity and biodiversity. The construction of 135 dams across the Mekong basin and the development of delta-based flood prevention systems have caused public concern given possible threats on the stability of agricultural and ecological systems in the floodplains. Mekong dams store water upstream and regulate flow seasonality, while in situ flood prevention systems re-distribute water retention capacity in the floodplains. The main aim of this paper is to evaluate possible impacts of the recent development of both hydropower dams and flood prevention systems on hydrological regimes in the Mekong floodplains. An analysis of measured daily and hourly water level data for key stations in the Mekong floodplains from Kratie to the river mouth in Vietnam was conducted. Hydropower dam information was obtained from the hydropower database managed by the Mekong River Commission, and the MODIS satellite imagery was used to detect changes in flooding extent related to the operation of flood prevention systems in the Vietnam Mekong Delta. Results indicate that the upper part of the floodplains, the Cambodian floodplains, may buffer upstream dam impacts to the Vietnam Mekong Delta. Flood prevention up to date has had the greatest effect on the natural hydrological regime of the Mekong floodplains, evidenced by a significant increase of water level rise and fall rates in the upper delta and causing water levels in the middle delta to increase. The development of flood prevention systems has also effected spatial distribution of flooding as indicated via a time series analysis of satellite imagery. While this development leads to increase localized agricultural productivity, our historical data analysis indicates that development of one region detrimentally affects other regions within the delta, which could increase the risk of future conflicts among regions, economic sectors and the ecological value of these important floodplains.