Abstract In this work, a systematic method for conceptual design and multi-objective optimization of an energy-efficient and sustainable reactive/extractive distillation (RED) process is proposed to separate a ternary wastewater mixture with multi-azeotrope tetrahydrofuran/ethanol/water. Conceptual design of the proposed scheme is carried out by the analysis of thermodynamic feasibility (e.g., residue curve maps and iso-volatility line). In the proposed process, the component of water in the ternary system is firstly removed by adding the reactant in a reactive distillation column and the remaining binary azeotropic mixture is then separated via ED. During the ED process, the best entrainer dimethyl sulfoxide could be determined via the comparison of iso- and uni-volatility. An improved multi-objective genetic algorithm is employed for optimizing the established process with some key decision variables (e.g., feed locations and distillate rate). The results illustrated that the economic and environmental benefits of the proposed RED process will be greatly improved.