The separation of cresol isomers is one of the significant issues in the utilization of crude phenols. In this work, ionic liquids (ILs)-based extractive distillation process was proposed to obtain high purity p-cresol and m-cresol. The multiscale methodology of screening ILs entrainer was established via the combination of quantum chemistry calculation, thermodynamic analysis, process optimization and energy-economic analysis. The valuable contributions of this work were to reveal ILs structure effects and mechanisms on enhancing the separation efficiency. This work aimed to compare organic solvent triethylene glycol (TEG) and ILs 1‐ethyl‐3‐methylimidazolium trifluoromethanesulfonate ([Emim][TfO]) or 1‐ethyl‐3‐methylimidazolium tetrafluoroborate ([Emim][BF4]) processes by considering techno-energy-economic aspects. Compared with TEG process, the [Emim][TfO] and [Emim][BF4] processes save 38% and 24.4% of total energy cost (TEC), respectively, and the total annual cost (TAC) can be reduced by 26.2% and 20.6%, respectively. [Emim][TfO]-based extractive distillation has been proved to be a promising green process for separation of cresols mixtures on the view of industrial applications.