Ionic liquids (ILs) of 1-ethyl-3-methylimidazolium acetate ([EMIM][OAC]), 1-ethyl-3-methylimidazolium proline ([EMIM][PRO]), and N,N,N-dimethyl-butylethanol amine glycolic acid ([N 1,1,4 C 2 OH][GAC]) are selected as entrainers for the extractive distillation to separate the mixture of acetonitrile and water based on the COSMO-RS method. The isobaric vapor−liquid equilibrium of ternary mixtures containing ILs at atmospheric pressure is determined, verifying that the used ILs can break the azeotropy of acetonitrile and water. On the basis of the thermodynamic analysis, a typical extractive distillation process is designed with Aspen Plus to evaluate the competitiveness of IL entrainers in separation performance. Significant savings of entrainer and energy, in which the solvent ratios in moles reduce from 0.94 to 0.09, 0.12, and 0.12 and the overall heat duties on the reboiler decrease 24.9, 17.5, and 15.4% for [EMIM][OAC], [EMIM][PRO], and [N 1,1,4 C 2 OH][GAC], respectively, can be achieved compared with those of ethylene glycol used as the entrainer.