Abstract. River tributaries have a key role in the biophysical functioning of the Mekong Basin. Of particular interest are the Sesan, Srepok, and Sekong (3S) rivers, which contribute nearly a quarter of the total Mekong discharge. Forty two dams are proposed in the 3S, and once completed they will exceed the active storage of China's large dam cascade in the Upper Mekong. Given their proximity to the Lower Mekong floodplains, the 3S dams could alter the flood-pulse hydrology driving the productivity of downstream ecosystems. Therefore, the main objective of this study was to quantify how hydropower development in the 3S, together with definite future (DF) plans for infrastructure development through the basin, would alter the hydrology of the Tonle Sap's Floodplain, the largest wetland in the Mekong and home to one of the most productive inland fisheries in the world. We coupled results from four numerical models representing the basin's surface hydrology, water resources development, and floodplain hydrodynamics. The scale of alterations caused by hydropower in the 3S was compared with the basin's DF scenario driven by the Upper Mekong dam cascade. The DF or the 3S development scenarios could independently increase Tonle Sap's 30-day minimum water levels by 30 ± 5 cm and decrease annual water level fall rates by 0.30 ± 0.05 cm day−1. When analyzed together (DF + 3S), these scenarios are likely to eliminate all baseline conditions (1986–2000) of extreme low water levels, a particularly important component of Tonle Sap's environmental flows. Given the ongoing trends and large economic incentives in the hydropower business in the region, there is a high possibility that most of the 3S hydropower potential will be exploited and that dams will be built even in locations where there is a high risk of ecological disruption. Hence, retrofitting current designs and operations to promote sustainable hydropower practices that optimize multiple river services – rather than just maximize hydropower generation – appear to be the most feasible alternative to mitigate hydropower-related disruptions in the Mekong.