Minimization of energy requirements in desalination processes is seen now as a necessary approach for future desalination plants. This concerns reducing the amount of produced sludge and saving of energy. Energy-exergy calculations might present a desirable approach for establishing a criterion based on which an optimum combination of desalination processes may be selected for operation. The thermodynamic property of exergy was combined with a mathematical model for multi-solute reverse osmosis systems to determine the optimum operating condition for an integrated nanofiltration (NF)-reverse osmosis (RO) seawater desalination plant. This simulation analysis shows promising results for the integrated NF-RO process. The analysis could further be extended to other desalination technologies including the state-of-the-art technology of membrane distillation.