Being restrained by the limited peak capacity, one‐dimensional chromatography usually leads to an unsatisfactory separation with low purity of compounds in a complex mixture. To obtain more highly pure targets for standard reference and to discover new substances for structural elucidation, two‐dimensional chromatography is more and more prevalent in many fields. As few metrics on assessment of the preparative capability of two‐dimensional chromatographic separations are reported, a methodology of in silico screening of various two‐dimensional chromatographic separations with a minimal number of experiments was demonstrated in this work, which was based on three descriptors including the occupation rate of peaks and system homogeneity of a two‐dimensional separation space, and the minimal distance of all nearest‐neighbor distances of peaks. Combining the advantages of counter‐current chromatography and liquid chromatography, we elaborated the methodology by employing off‐line comprehensive two‐dimensional counter‐current chromatography with liquid chromatography to be in silico screened for separation of four saponins from Panax notoginseng at an analytical scale to simulate the case of preparative scale transfer. The predictive results were presented by two‐dimensional contour plots and verified by experiments. The result showed that the experimental results were in general accord with the predictive results.