Abstract. A number of large hydropower dams are currently under development or in an advanced stage of planning in the Magdalena River basin, Colombia, spelling uncertainty for the Mompós Depression wetlands, one of the largest wetland systems in South America at 3400 km 2 . Annual large-scale inundation of floodplains and their associated wetlands regulates water, nutrient, and sediment cycles, which in turn sustain a wealth of ecological processes and ecosystem services, including critical food supplies. In this study, we implemented an integrated approach focused on key attributes of ecologically functional floodplains: (1) hydrologic connectivity between the river and the floodplain, and between upstream and downstream sections; (2) hydrologic variability patterns and their links to local and regional processes; and (3) the spatial scale required to sustain floodplain-associated processes and benefits, like migratory fish biodiversity. The implemented framework provides an explicit quantification of the nonlinear or direct response relationship of those considerations with hydropower development. The proposed framework was used to develop a comparative analysis of the potential effects of the hydropower expansion necessary to meet projected 2050 electricity requirements. As part of this study, we developed an enhancement of the Water Evaluation and Planning system (WEAP) that allows resolution of the floodplains water balance at a medium scale (∼ 1000 to 10 000 km 2 ) and evaluation of the potential impacts of upstream water management practices. In the case of the Mompós Depression wetlands, our results indicate that the potential additional impacts of new hydropower infrastructure with respect to baseline conditions can range up to one order of magnitude between scenarios that are comparable in terms of energy capacity. Fragmentation of connectivity corridors between lowland floodplains and upstream spawning habitats and reduction of sediment loads show the greatest impacts, with potential reductions of up to 97.6 and 80 %, respectively, from pre-dam conditions. In some development scenarios, the amount of water regulated and withheld by upstream infrastructure is of similar magnitude to existing fluxes involved in the episodic inundation of the floodplain during dry years and, thus, can also induce substantial changes in floodplain seasonal dynamics of average-to-dry years in some areas of the Mompós Depression.