The efficient separation of alcohol-nitrile azeotropes produced in chemical production is a difficult problem in the chemical industry, and the widely used extractive distillation techniques in this field have put forward further requirements for the selection of extractants and mechanism analysis. The COSMO-RS model can be used to predict the thermodynamic properties of the fluid through quantitative calculation, and select the ionic liquids (ILs) extractant agent suitable for a certain system from a large number of possible solvents, which can significantly reduce the experimental amount and enhance the research efficiency. By comparing the model prediction value with the experimental value, the accuracy of the COSMO-thermX software in predicting the separation of alcohol and nitrile azeotropes by ionic liquid has been verified. Based on the COSMO-RS model, with the separation selectivity of ILs, the influence of ILs on the relative volatility of isopropyl alcohol (IPA)-acetonitrile (MeCN) near boiling point and the solubility of ILs to IPA as indexes, the effects of 456 ILs composed of 24 cations and 19 anions on the separation of IPA-MeCN azeotrope were calculated and analyzed. The results showed that ammonium tetraethylacetate ([N2,2,2,2][Ac]) was the best extractant. The interaction between IPA-MeCN molecules in the mixture and [N2,2,2,2][Ac] was studied by means of excess enthalpy analysis, interaction energy analysis and weak interaction analysis, and the separation mechanism of [N2,2,2,2][Ac] as an extractant for separating IPA-MeCN at molecular level was discussed, and the results showed that the interaction between [N2,2,2,2][Ac] and IPA was stronger than that with MeCN, thereby accelerating the disruption of the original azeotropic structure. The assistance of the COSMO-RS model in screening ILs extractants and analyzing separation mechanisms provided important information for further understanding the function of ionic liquid in azeotropic system separation, and had important reference value for the development of novel extractive distillation technologies.