• Fair comparison between single-stage and multistage reverse electrodialysis. • New “saving the gradient” electrical control strategy improves process performance. • To harvest energy from river water and seawater, applying two stages is optimal. • Reducing stack pressure drops favors multistage application. Reverse electrodialysis has been established as a promising method to harvest salinity gradient energy. To achieve market viability, an optimum process configuration is needed, in addition to material and stack development, to increase energy efficiency without compromising power density. Multistage reverse electrodialysis is a practical strategy providing several degrees of freedom, such as independent electrical control of the stages, asymmetric staging, and different configurations. This study tests a two-stage configuration experimentally, using seawater and river water (NaCl only), at several residence times and changing the electrical control. Furthermore, the results are compared with a numerical model that is subsequently used to predict the behavior of alternative multistage configurations. The results show that multistage reverse electrodialysis yields higher gross power density and energy efficiency than a single-stage configuration fed with the same salinity gradient. A new strategy named “saving the gradient” (i.e., lowering the discharge current in the first stage) increased the gross overall performance of the two stages up to 17% relative to single-stage and up to 6% relative to a sequentially optimized two-stage system. Modeling different configurations revealed that only two stages are needed when feeding seawater and river water. When retrieving 40% net energy efficiency, the net power density for a single stage is 0.86 W∙m −2 and 0.94 W∙m −2 for a two-stage system, representing an improvement of 9%. Multistage reverse electrodialysis is therefore a viable concept to enhance power and energy efficiency, and benefits from optimization through electrical control.