This review focuses on the antioxidant and prooxidant activities of polyphenols, particularly their interactions with iron both in vitro and in vivo. It provides an overview of oxidative stress and the Fenton reaction, along with the chemistry of iron binding by catecholate, gallate, and semiquinone ligands. The stability constants, UV–vis spectra, stoichiometries, and rates of iron oxidation by O2 upon polyphenol binding are discussed. The radical scavenging mechanisms of polyphenols unrelated to iron binding, their interactions with copper, and the prooxidant activity of iron–polyphenol complexes are also covered. The review highlights the importance of iron-binding properties in the antioxidant activity of polyphenols and their potential applications in preventing oxidative stress-related diseases. Additionally, it explores the cytoprotective effects of polyphenols related to iron-binding, their protective effects in blood and plasma, and their potential in treating neurodegenerative diseases. The structure–activity relationships (SARs) of polyphenols related to iron binding are established, and the review suggests future directions for clinical trials and further research.This review focuses on the antioxidant and prooxidant activities of polyphenols, particularly their interactions with iron both in vitro and in vivo. It provides an overview of oxidative stress and the Fenton reaction, along with the chemistry of iron binding by catecholate, gallate, and semiquinone ligands. The stability constants, UV–vis spectra, stoichiometries, and rates of iron oxidation by O2 upon polyphenol binding are discussed. The radical scavenging mechanisms of polyphenols unrelated to iron binding, their interactions with copper, and the prooxidant activity of iron–polyphenol complexes are also covered. The review highlights the importance of iron-binding properties in the antioxidant activity of polyphenols and their potential applications in preventing oxidative stress-related diseases. Additionally, it explores the cytoprotective effects of polyphenols related to iron-binding, their protective effects in blood and plasma, and their potential in treating neurodegenerative diseases. The structure–activity relationships (SARs) of polyphenols related to iron binding are established, and the review suggests future directions for clinical trials and further research.