The effective recovery of n-butanol (BuOH) and toluene from wastewater via sustainable separation process is critical to promote environmental protection and resource utilization. In this work, we propose a comprehensive methodology to develop a natural decanting coupled with pressure-swing distillation (NDPSD) for the azeotropic separation of BuOH/toluene/water system. Firstly, the thermodynamic topologic insights are employed to analyze the feasibility of the NDPSD. Secondly, conceptual design involving the understanding of mass balance lines, the liquid–liquid envelope, and distillation boundaries were applied to develop initial design of the NDPSD with two different separation sequences (i.e., configurations). Then, both initial designs are optimized to obtain the optimum column configurations via an improved non-sorting genetic algorithm, with the total capital and operating cost as dual objective function. Finally, both optimized schemes are heat-integrated for the purpose of energy conservation. The performance of all the developed configurations were examined using three indicators, i.e., economic, environmental, and energy efficiency, and our results revealed that the heat-integrated configuration B with separation sequence of water → BuOH → toluene provides the best economic, environmental, and thermodynamic efficiency.