Reverse Osmosis (RO) has become one of the world’s leading technologies for desalination purposes. The technical maturation of membrane materials and hydraulic devices has further enabled its deployment across many applications ranging from municipal freshwater production to industrial wastewater reuse. This widespread and increasing deployment of RO, often with sector-specific objectives and tailored configurations, coupled with the growing use of renewable energy sources, has made it quite common for RO treatment plants to operate outside their intended design. Accommodating the scale and spatial salinity range at which these processes must operate has resulted in current modelling approaches no longer being suitable in fully characterising plant process variables over an extended range of operation. These modelling inaccuracies, originating from the assumption of certain fixed parameters, has compounding effects on other subsequent areas of the RO system, ultimately leading to misinformed predictions of membrane performance, energy efficiency and plant running costs. Importantly, the aforementioned limitations hinder the development of new treatment strategies over a wider range of operation. A pilot scale RO process was designed and developed. Subsequently, a detailed experimental study was undertaken to validate relevant physicochemical, electromechanical and economic models, to better understand the interplay of certain technical and economic process variables. The final outputs from all three models combine to form the Performance–Power–Economic (PPE) methodological approach to help improve upon the efficacy, efficiency and feasibility of RO plant configurations over a wide range of operating conditions. The proposed method can be indirectly applied to new or pre-existing RO systems to greater define: (a) membrane separation performance; (b) electrical and hydraulic component efficiencies and (c) the feasibility and cost-effectiveness of overall treatment.