Pressure retarded osmosis (PRO) power plants generate power from mixing of saltwater and freshwater by means of membrane systems. In this paper we present a model which describes the complete power station, suitable to optimize the power station both with respect to system parameters and in operating conditions. Special attention is dedicated to the flow model of the “core” membrane unit. It considers the relevant water and salt flows in the system. It also accounts for irreversible losses in the flow across the membrane as well as through the membrane unit, and in the surrounding pump-turbine system. The model represents a compromise between needed complexity (including the most relevant chemo-physics) and simplicity to allow rapid simulations which is an important prerequisit for optimisation. Finally, we optimise numerically, i.e., the net power output (per membrane area) with respect to geometric parameters, membrane parameters as well as operational parameters such as the applied pressure settings during operation.