The development of clean and green separation technologies has become a key scientific issue in the chemical industry. Because of the wide applicability of ionic liquids (ILs) as green and recyclable extractants, their abilities to extract and separate n-butanol from octane were explored in this work. Based on quantum chemical methods and the COSMO-SAC model, the surface charge density distributions of 22 cations, 19 anions, octane, and n-butanol were calculated. Moreover, the infinite dilution activity coefficients of octane-n-butanol-IL systems were calculated. The distribution coefficients and separation coefficients were also determined. ILs with strong extraction effects (i.e., [Bmim][HSO4], [Bmim][NO3], and [Bmim][OTf]) were used to explore the separation mechanism at the molecular scale; this was conducted by analyzing charge density, bond energy, and bond length of intermolecular interactions. The liquid–liquid equilibrium data of octane-n-butanol-ILs systems were measured, and the distribution coefficients and separation coefficients of each system were calculated. The experimental data were regressed using the NRTL model to obtain the corresponding binary interaction parameters. A process for separating the azeotropic octane and n-butanol systems using ILs was proposed. This process was simulated and optimized using the Aspen Plus 11 software. In addition, the total annual cost was calculated. This work lays the foundation for the screening of green and clean separation solvents.