In summary, a data-driven approach provided physical insights into the mechanisms of ion selectivity in ion-binding molecular complexes. By studying the energetic preferences of a curated dataset of 563 molecular complexes binding to K + , Na + , and Li + using DFT, we found that binding preferences are related to ion size. Complexes prefer to exchange to an adjacent ion in the size sequence K + > Na + > Li + rather than to the species that is more dissimilar in size. While this observation follows intuition, we identified unique complexes which deviate from this trend and hold significant promise for distinctive forms of selectivity in materials, namely those with planar coordinating atoms that could preferentially bind K + and Li + over Na + , compounds with large ring sizes despite small coordination numbers that would disfavor Li + binding in comparison to Na + or K + , and complexes with N coordinating atoms which favor Li + over Na + or K + . Additionally, we showed that the majority of the differential binding energy originates from chemical interaction rather than molecular reorganization. Our trained ML models revealed that both electronic and geometric features play critical roles in predicting the differential binding energy, and neither category strongly dominates the prediction. When comparing the most important features for predicting ion selectivity, the feature that corresponds most to the ability of smaller ion complexes to accommodate larger ions is the distance of the coordinating atoms to the ion, whereas properties of the electron density, including Hirshfeld charge and average local ionization energy are the most important features for the reverse process. Taken together, these observations suggest opportunities to target the selective binding of either larger or smaller ions by either tuning the electronic structure or constraining coordinating environments to smaller distances, respectively.