The rapid construction of water infrastructure in the Mekong Basin, including upstream dams and delta-based flood prevention systems, is raising public concerns due to potential impacts on ecosystems and agricultural productivity. Sixty eight multi-purpose dams, accounting for 71 billion m3 of active volume in total, have been built since the 1960s. It is estimated that an additional sixty seven dams with 68 billion m3 of active volume will be operational in the next ten years, resulting in highly regulated downstream flows. The Normalized Difference Vegetation Index (NDVI) was analyzed based on the MODIS satellite sensor images (temporal solution of 16-days), which indicates that the flood protected areas has increased nearly three times in the past 14 years (from 2000 to 2014) in the upper part of the Vietnam Mekong Delta. Flood prevention systems were built to increase rice production from two to three crops a year and to protect residential areas in the floodplain. This development has caused a significant reduction in water retention capacity of the floodplain and higher water levels in adjacent areas. Changes in historical water levels along the lower Mekong River ranging from the most upstream (Kratie) to the middle (Kampong Cham, Phnom Penh, Tan Chau, Chau Doc and Can Tho) and the coast station (Vam Kenh) were also analyzed. Historical alterations in water level patterns (maximum, minimum, rise rate, fall rate and fluctuations) over time were then associated with the development of either dams or flood prevention systems. Rise rates at the Kratie station in the upper part of the floodplain gradually decreased by 25% between 1960 and 2013, but remained rather constant at Phnom Penh, the middle of the floodplain. In the lower part of the floodplain, alterations to water levels, rise rates and fall rates have been higher since 2006, and this corresponds to the operation of flood prevention projects in the Vietnam Mekong Delta. The impact of existing upstream dams on the Vietnam Mekong Delta is currently buffered by the Tonle Sap Lake and Cambodian floodplains. It can be concluded that the development of flood prevention systems is currently a key driver of water level changes in the delta.