Although desalination market is today dominated by Seawater Reverse Osmosis (SWRO), important technological issues remain unaddressed, specifically: relatively low water recovery factor (around 50%) and consequent huge amount of brine discharged, and energy consumption (3–5 kWh/m3) still far from the minimum thermodynamic value (∼1 kWh/m3). Herein, the energy performance of an innovative systems combining SWRO, Membrane Distillation (MD) and Reverse Electrodialysis (RED) for simultaneous production of water and energy is investigated. The valorization of hypersaline waste brine by Salinity Gradient Power production via RED and the achievement of high recovery factors (since MD is not limited by osmotic phenomena) represent a step forward to the practical implementation of Zero Liquid Discharge and low-energy desalination. The analysis is supported by lab-scale experimental tests carried out on MD and RED over a broad set of operational conditions. Among the different case studies investigated, exergetic efficiency reached 49% for the best scenario, i.e. MD feed temperature of 60 °C, MD brine concentration of 5 M NaCl, RED power density of 2.2 W/m2MP (MP: membrane pair). Compared to the benchmark flowsheet (only SWRO), up to 23% reduction in electrical energy consumption and 16.6% decrease in specific energy consumption were achieved when including a RED unit. The analysis also indicates that optimization of thermal energy input at the MD stage is critical, although it can potentially be fulfilled by low-grade waste heat or solar-thermal renewable sources. Overall, the proposed integrated system is coherent with the emergent paradigm of Circular Economy and the logic of Process Intensification.