Multi-stage reverse electrodialysis (MSRED) offers a promising way for efficient salinity gradient energy harvesting. Here, an improved model of the MSRED system under serial control strategy is proposed. The technical–economic analysis is conducted with considering discount, depreciation and different regional tax and electricity price levels under the maximum net power output conditions. Results reveal that net power output and energy efficiency both increase first with increasing stage numbers, reach their maximum values, and then decrease. For 5 M/0.05 M solutions, the optimal net power output of 4.98 kW is obtained at the stage number n = 12. The optimal stage number corresponding to the maximum net power increases with increasing feed solution concentrations. Due to the compromise between net power generation and capital cost, there exist optimal stage numbers leading to the lowest LCOE and largest NPV, respectively. Higher feed solution concentration can significantly decrease the system LCOE and increase the NPV. The optimal stage number corresponding to the maximum NPV increases with increasing feed solution concentrations. In Germany, for 5 M/0.05 M solutions, the lowest LCOE of 0.061 €·kWh−1 is achieved at n = 3 while the highest NPV over the system lifecycle of 52,005 € is obtained at n = 8. Lower tax, higher electricity price, appropriate membrane price and stage numbers, and high salinity gradient sources can significantly accelerate the commercial completeness of the MSRED systems.