Natural antioxidants products are widely distributed in food and medicinal plants. These natural antioxidants, especially polyphenols, exhibit a wide range of biological activities including anti-cancer, anti-inflammatory, and anti-atherosclerosis activities. Pomegranate (Punica granatum L.) is a rich source of polyphenolic components. The purpose of this study was to characterize the phenolic composition and flavonoids and anthocyanin content of different parts (peel and aril) of the Sefri variety of pomegranate. Our results showed that Peel extract was richer in these compounds than that of the Arils, especially in Punicalagin (A and B). DPPH free radical scavenging, reducing power (FRAP), β-carotene bleaching, and hydrogen peroxide scavenging assays revealed a greater dose-dependent activity of pomegranate peel phenolic extract (PPPE) compared to pomegranate aril phenolic extract (PAPE). PPPE was also more potent than PAPE concerning its ability to inhibit conjugated diene formation and to reduce α-tocopherol disappearance induced by CuSO4-mediated LDL peroxidation. Interestingly, both extracts (PPPE and PAPE) significantly inhibited lipid peroxidation and the formation of reactive oxygen species (ROS) in stressed J82 human bladder cancer cells. These results reflect the protective effects that this Moroccan variety of pomegranate can provide against the development of metabolic disorder, cancer, atherosclerosis, and cardiovascular disease. Given these properties, further studies should be undertaken to investigate possible applications of Sefri pomegranate extracts in the fields of food preservation and health supplements.