Polyphenols form nanofilms with transition metal ions by coordination‐driven assembly. The as‐formed metal‐polyphenol nanofilms can degrade in the presence of chelating ligands that exhibit high stability constant with the nanofilm‐forming metal ions. We have demonstrated the degradation of Fe(III)‐tannic acid nanofilms with hydroxyketone ligands, such as maltol, kojic acid, and deferiprone, which exhibit high availability and excellent cytocompatibility. The concentration screening experiments have been performed with different ligand concentrations ranging from 1 mM–25 mM. It is important to note that only deferiprone degrades Fe(III)‐TA nanofilms even at 1 mM, and it retains the degradation activity at pH 7.4. The characteristic degradation activity of hydroxyketone ligands to Fe(III)‐TA nanofilms may depend upon their pKa value and stability constant. The degradation studies herein are attractive for the development of biomedical applications utilizing metal‐polyphenol nanofilms as a sacrificial template.