In Europe and North America, up to 90% of floodplains have become extensively regulated, occupied, and polluted, with important consequences in the floodplain ecosystem. For this reason, exploring the processes that drive ecosystem structure and functionality is of great relevance in the development of management plans to effectively counteract the influence of negative human impacts. To address these needs, the present study aims to provide a solid background for river-floodplain restoration based in the response of aquatic communities, especially macroinvertebrates, to changes in hydrological connectivity, environmental factors and human pressure across the floodplain of a Mediterranean river.The lateral hydrological connectivity was found to be the key factor structuring the habitats and aquatic communities of the Middle Ebro floodplain, while turbidity, salinity and nutrient status were secondary drivers. These factors created a template for the aquatic community development that enabled predictions about the taxonomic and functional patterns in those aquatic communities more likely to occur under particular conditions. In the Middle Ebro River, there are very few possibilities of new wetlands creation, while the diversity and functionality of the remaining ones are threatened by the limited hydrological connectivity. The objective of floodplains restoration in the Middle Ebro River should thus consist in re-establishing a wide range of wetland types in accordance with the river-floodplain potential of sustainability.