The Punica granatum L. is an erect shrub also called as pomegranate belongs to the family Punicaceae which is a rich source for polyphenols with high antioxidant capacity, and it has been used for medicinal purposes since from the ancient times. The fruit is a globose berry, crowded by persistent calyx lobes with leathery pericarp and numerous seeds which are surrounded by a pink to red transparent, juicy, and acidic pleasant pulp. It's use in ancient cultures including Ayurvedic, Greek, Unani, and Egyptian had documented. In the recent times, pomegranate polyphenols have received significant attention of consumers, industry, and researchers. In the published literature, several research studies have shown that pomegranate has exert significant antiatherogenic, antioxidant, anticancer, anti-inflammatory, antibacterial, and cardioprotective effects. In this chapter pomegranate polyphenols existance, health benefits, proposed mechanism of polyphenol cleavage by cellular and/or bacterial effects, and the safety studies have discussed in detail.