A new selection method is developed for group contribution combined with molecular design for an extractant in liquid–liquid extraction. Based on the definition of extractant selectivity, the UNIversal Functional Activity Coefficient-group contribution method was first used for model building to preselect functional groups. Then, the molecular structures of extraction solvents were designed and determined according to the basic principle of group combination. Finally, the selectivity and distribution coefficients of candidate designed molecules were calculated to screen out the ideal extractant. For verification, it was applied to simulate potential extraction solvents for three typical biphasic systems and calculate related phase equilibrium data for all the components. Calculated results and experimental verification for the screened extraction agent proved that it was a good computational strategy for practical application in classical water–organic solvent equilibrium systems together with liquid–liquid separation compared with conventional ways.