The purification of isomer monomers with high purity is extremely important, particularly in the fine chemical industry, pharmaceutical industry, and so on. Herein, a selective cocrystallization (SCoC) technology based on non-covalent interactions between the target compound and cocrystal conformers was developed to effectively separate isomer mixtures. The unique and efficient selectivity nature of conformers and the general applicability of the selective cocrystallization method was tested through separating and purifying cresol isomer mixtures, pyridinecarboxamide isomer mixtures, and cis−/trans-butenedioic acid mixtures. Moreover, the nature of selective recognition to cocrystallize was confirmed both in the solution and solid states. Thus, this study demonstrates the feasibility of this novel SCoC technology, which is a new method for separating isomer mixtures.