Pressure-retarded osmosis (PRO) is a promising technique for osmotic power generation by recovering salinity gradient from high concentration effluents. Prior research has shown that the PRO systems integrating multiple draw/feed streams can achieve a 20+% increase in energy recovery compared with standalone design. However, to date few approaches have been developed to fully utilize this potential. Herein, we propose a novel method for the multi-stream PRO system that optimizes its modules (mass exchangers) layout as a mass exchanger network in three steps. In the first step, the maximum energy conversion is determined and used as an energy target for subsequent mass exchanger network synthesis. In accordance with the energy target, the second step establishes the optimal match of streams by introducing three criteria of “number of streams”, “KP coefficient”, and “maximum mass exchange”. The third step balances the system complexity and energy recovery by relaxing the energy target. An economic model is formulated to evaluate the performance of PRO systems. Several multi-stream PRO system design examples are presented to illustrate the proposed method. Results indicate that the integrated designs generally outperforms the standalone designs by 11.75–21.65 % for energy recovery, and achieves better economic performance and higher power density for large osmotic pressure difference cases with minimum net osmotic pressure difference greater than 0.8 MPa. A minimum levelized cost of energy of 0.1364 $/kWh can be achieved by the proposed design method, constituting a 6.95 % reduction compared with the standalone design.