In this research, low strength synthetic wastewaters with chemical oxygen demand less than 300 mg L−1 were treated at different concentrations in a bioelectrochemical desalination process. A process optimization model was utilized to study the performance of the photosynthetic bioelectrochemical desalination process. The variables include substrate (chemical oxygen demand) concentration, total dissolved solids, and microalgae biomass concentration in the cathode chamber. Relationships between the chemical oxygen demand concentration, microalgae, and salt concentrations were evaluated. Power densities and potential energy benefits from microalgal biomass growth were discussed. The results from this study demonstrated the reliability and reproducibility of the photosynthetic microbial desalination process performance followed by a response surface methodology optimization. This study also confirms the suitability of bioelectrochemical desalination process for treating low substrate wastewaters such as agricultural wastewaters, anaerobic digester effluents, and septic tank effluents for net energy production and water desalination.