Obesity is an urgent social problem and new functional foods providing polyphenols and dietary fibers (DF) may be promising tools to modulate oxidative stress, inflammation and energy homeostasis. Pomegranate peels (PPe) are an agro-industrial by-product containing polyphenols such as ellagitannins (ETs), gallic acid (GA), ellagic acid (EA) and its derivatives (EAs), as well as DF. In this study, PPe enriched cookies (PPeC) were developed, and the bioaccessibility as well as the ability of their polyphenols to exert antioxidant activity along the Gastro-intestinal Tract (GiT) and to modulate digestive enzymes were evaluated in vitro. Data showed that the potential bioaccessibility of ETs was 40% lower from PPeC than PPe whereas EAs’ and GA bioaccessibility increased by 93% and 52% for PPeC compared to PPe. The concentration of the polyphenols at each digestion step was associated with the total antioxidant capacity of the potentially bioaccessible material. Moreover the polyphenols released in the simulated duodenal phase upon PPeC digestion exhibited inhibitory activity towards α-glucosidase, α-amylase and lipase, being α-glucosidase > α-amylase > lipase. In conclusion, the data demonstrated that the inclusion of PPe at 7.5% in a bakery product potentially led to a high bioaccessibility of ETs’ degradation products (mainly EA and EAs) in the duodenum, with a consequent antioxidant protection along the GiT and modulation of glucose metabolism. Further human studies are warranted to evaluate whether these effects also occur in vivo.