The RO process cannot be operated in a thermodynamically ideal state, and in general, additional pressure is required. In addition, multi-stage RO involves an increased number of design factors compared to single-stage RO, and the feed pressure and SEC of multi-stage RO have a complex correlation with the design conditions. In this study, a comprehensive assessment was conducted to evaluate the advantages of multi-stage RO over single-stage RO. Specifically, we found ranges where the multi-stage process loses its energy advantage over the single stage depending on the total recovery rate and suggested a break-even point in terms of energy, theoretically and practically. Furthermore, we investigated the impact of design factors such as stage recovery rate, number of elements per vessel, and total number of membranes applied to each stage on energy consumption, and we also presented the optimal conditions for the design factors with theoretical support. Finally, we compared all configurations of single and multi-stage RO processes under optimal conditions and suggested an energy-efficient process. These investigations could offer valuable design heuristics for optimal multi-stage RO setups and provide insights into the advantages of multi-stage RO processes over single-stage RO processes.