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. Annual large-scale inundation of floodplains and 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 present a comparative analysis of the potential effects of hydropower expansion to meet projected electricity requirements by 2050, in terms of 1) basin-level implications of cumulative changes in streamflow regime, sediment trapping, and loss of river connectivity, and 2) the impact of upstream regulation on the hydrologic dynamics of the Mompós Depression wetlands at a monthly to decadal scale. To this end, we developed an enhancement of the Water Evaluation and Planning system (WEAP) that allows resolution of the Mompós Depression floodplains water balance at a medium scale (~1000 to 10 000 km2) and evaluation of the potential impacts of upstream water management practices. Our results indicate that 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 periods and, thus, can also induce substantial changes in floodplain seasonal dynamics of average-to-dry years in some areas of the Mompós Depression.