Though ubiquitous in nature, polyphenols gained scientific prominence only after the pioneering work of researchers like E. Fischer and K. Freudenberg, who demonstrated their potential beyond traditional applications, such as in the leather industry. Today, these bioactive compounds are recognized for their diverse therapeutic roles, including their use as adjuvants in cancer treatment, cancer prevention, and their anti-inflammatory and antioxidant properties. Additionally, polyphenols have demonstrated benefits in managing obesity, cardiovascular diseases, and neuromodulation. Their synthesis is influenced by environmental and genetic factors, with their concentrations varying based on the intensity of these variables, as well as the stage of ripening. This review provides a comprehensive overview of polyphenols, covering their classification, chemical structures, and bioavailability. The mechanisms influencing bioavailability, bioaccessibility, and bioactivity are explored in detail, alongside an introduction to their bioactive effects and associated metabolic pathways. Specific examples, such as the bioavailability of polyphenols in coffee and various types of onions, are analyzed. Despite their promising biological activities, a significant limitation of polyphenols lies in their inherently low oral bioavailability. However, their systemic circulation and the bioactive by-products formed during digestion present exciting opportunities for further research and application.