It is well known that plant-derived polyphenols are biologically relevant for human health both for their direct antioxidant activity and for their effects in the modulation of intracellular signals. Experts in this field have become aware of the need to carefully evaluate the effectiveness of these compounds in vivo, because of their absorption and metabolism kinetics once ingested. Indeed, it has been established that phenolic compounds are exposed to extensive metabolism in the human body, and their bioavailability is poor with respect to their metabolites. Thus, considering the biological activity of parent compounds, instead of that of their metabolites, is the major concern in relation to the studies on these molecules, especially in vitro. Recently, the main metabolites of polyphenols have become the subject of manifold research studies, which have revealed their beneficial effects particularly as antioxidant, anti-inflammatory and anticancer agents. They have also been investigated for their role in the prevention of cardiovascular and neurodegenerative diseases. The goal of this review is to emphasize the importance of the main in vivo formed metabolites of polyphenols for their potential benefits in relation to human health, showing the most significant outcomes of in vivo and in vitro studies carried out in the last few decades.