Reverse osmosis (RO) is one of the major technologies for seawater desalination, while pressure retarded osmosis (PRO) is a promising technology for power generation. The RO desalination plant has the problems of extensive energy consumption and brine discharge, which can be alleviated by hybridizing the RO process with the PRO process as an integrated RO/PRO system. This study is to pursue a higher goal, that is, the power generated by the PRO unit can provide the energy consumption required for the entire hybrid system. Namely, the hybrid membrane osmosis system can achieve stand-alone operation (without external energy supply) for seawater desalination. In this study, mathematical programming models are developed for the design, operation, and control of the stand-alone hybrid membrane osmosis desalination systems. First, optimal design for two configurations of the hybrid osmosis system (i.e., RO-PRO and PRO-RO systems) is investigated. The result shows that the PRO-RO system is a more favorable design configuration for stand-alone desalination. Because the membrane system operation is bound to be affected by membrane fouling, this study explores the effects of membrane fouling on the stand-alone operation of the systems, and proposes an open-loop control scheme to determine the optimal operating strategy under membrane fouling. Finally, a closed-loop control scheme of model predictive control is proposed for the PRO-RO system to instantly compensate for the effects of unknown disturbances and modeling errors on the stand-alone operation of the desalination system.