<p>Antioxidants play a vital role in neutralizing oxidative stress and maintaining cellular homeostasis. However, emerging evidence highlights their paradoxical nature, while beneficial in regulated doses, excessive or inappropriate supplementation may contribute to disease progression, chemoresistance, and redox signaling disruption. This narrative review examines both the protective and potentially harmful roles of antioxidants in toxicology, with a focus on therapeutic challenges and clinical implications. We reviewed relevant peer-reviewed articles, preclinical and clinical studies, and systematic reviews published between 2012 and 2024, using databases such as Scopus, Web of Science, and PubMed. Key findings indicate that antioxidants can inadvertently promote cancer progression under certain conditions, complicate treatment outcomes, and interfere with endogenous redox balance. The review explores precision medicine approaches for tailoring antioxidant therapy, as well as their effects on chronic diseases such as neurodegeneration and cardiovascular disorders. Further, we assess the role of antioxidants in mitigating oxidative damage induced by environmental toxicants like heavy metals and air pollutants. Innovative strategies, including nanotechnology-based delivery systems, are discussed as promising tools to enhance therapeutic specificity and minimize off-target effects. Overall, this review underscores the importance of understanding the nuanced role of antioxidants in toxicology to ensure their safe and effective clinical use, and it outlines critical directions.</p> Graphical Abstract <p></p>