AbstractThe deep separation between In(III) and Fe(III) ions is considered as an important technological challenge in the engineering fields. The In(III) ions are closer to the soft acid in terms of Lewis acidity due to the smaller polarizability and greater deformability than the Fe(III) ions, which facilitates the possibility of separating them. Herein, the Lewis basicity of the N‐containing adsorption sites is regulated by the fluorine‐containing group to better match with the In(III) ions rather than Fe(III) ions, causing a significant discrepancy in the binding of the adsorption sites to them. Moreover, targeted programmed desorption techniques based on the potential energy differences of the adsorption sites can achieve the deep separation of In(III) and Fe(III) ions, and reach an exceptional concentration of 20.7 mmol L−1 for In(III) ions in the initial desorption solution with extremely high mass ratio (mIn/mFe = 151.7). This work provides a novel technique for in‐depth separation of In(III) and Fe(III) ions from mixed systems, and a new strategy for separating metal ions with similar or close properties.