The Mekong river is one of the most complex river systems in the world that is shared by six nations in Southeast Asia. The river still remains relatively undammed (most existing dams are in the tributaries and are small), and its hydrology today is dominated by large natural flow variations that support the highly productive agricultural and riverine ecological systems; however, this is changing due to the alterations in land use and construction of new dams both in the tributaries the mainstream. Understanding the changes in surface water dynamics is therefore crucial to provide realistic future predictions of changes in downstream floodplain and riverine ecology due to the construction of dams in the upstream. While the existing dams have caused little impact on mainstream flows, those under construction and planned are likely to cause severe and potentially permanent damage to downstream hydro-agro-ecological systems, and adversely impact the livelihood of millions. Here, using hydrodynamic model simulations (CaMa-Flood), we show that the effects of flow regulation on downstream river-floodplain dynamics are relatively predictable along the mainstream Mekong, but flow regulations could potentially disrupt the flood dynamics in the Tonle Sap River (TSR) and small distributaries in the Mekong Delta. Results suggest that TSR flow reversal could cease if the Mekong flood pulse is dampened by 50% and delayed by one-month. While flood occurrence in the vicinity of the Tonle Sap Lake and middle reach of the delta could increase due to enhanced low flow, it could decrease by up to five months in other areas due to dampened high flow, particularly during dry years. Further, areas flooded for less than five months and over six months are likely to be impacted significantly by flow regulations, but those flooded for 5-6 months could be impacted the least.