The solvents for the separation of 2-methoxynaphthene and 2-acetyl-6-methoxynaphthalene were screened by computer using the solid-liquid equilibrium equation based on modified UNIFAC; according to the predicted values of separation factor and selection principles of suitable solvent, the promising candidates of appropriate solvents were determined as hexane, heptane, cyclohexane, and octane. The solubility and separation factor data of the two solid solutes in corresponding appropriate solvents were measured by static equilibrium method, and the average absolute value of relative deviation between the calculated separation factor values and experimental data is 8.1%, which indicates that the solid-liquid equilibrium equation based on modified UNIFAC is suitable for the separation solvents scanning of solid solute mixtures having similar molecular stereoscopic structures. Determination the appropriate separating solvents by the combination of computer high-throughput scanning and experimental verification can save the manpower, material, and financial resources as much as possible.