Polyphenols, a diverse group of bioactive compounds found abundantly in plant-based foods, have gained significant attention for their potential to modulate human drug metabolism through interactions with cytochrome P450 (CYP) enzymes. These enzymes, particularly isoforms such as CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2, are responsible for the biotransformation of a majority of pharmaceutical agents. Polyphenols can inhibit CYP activity via multiple mechanisms, including competitive, noncompetitive, and irreversible inhibition, depending on their structural characteristics and the specific isoform involved. Structure–activity relationships have revealed that hydroxylation patterns, lipophilicity, planarity, and glycosylation strongly influence CYP inhibitory potency. While in vitro studies demonstrate significant inhibition of CYPs by compounds such as amentoflavone, bergamottin, imperatorin, and apigenin, their clinical impact is often limited by low bioavailability and rapid metabolism. Nonetheless, high-dose supplements and concentrated extracts may pose a risk for drug interactions, particularly in populations with polypharmacy. Conversely, selective inhibition of CYPs by polyphenols offers potential therapeutic benefits, such as enhancing drug bioavailability or modulating procarcinogen activation. As research advances, a comprehensive understanding of polyphenol–CYP interactions is essential for optimizing therapeutic strategies and managing dietary-drug interactions in clinical practice.