The inhibitory potency of thirteen polyphenolic extracts obtained from vinification byproducts of Greek varieties of Vitis vinifera against glycogen phosphorylase (GP) has been studied by kinetic experiments. GP is an enzyme involved in glucose homeostasis and a molecular target for the discovery of new hypoglycemic agents. Studies have shown that all extracts display significant inhibitory potency for GP in vitro with IC₅₀ values in the range of low μg/mL. X-ray crystallographic analysis of GP crystals soaked with two of these extracts revealed that the most active ingredient is quercetin which binds at novel binding site, distinct from the other known sites of the enzyme. One of the most potent of the studied extracts had also a moderate effect on glycogenolysis in the cellular lever with an IC₅₀ value of 17.35 μg/mL. These results highlight the importance of natural resources in the quest for the discovery of new hypoglycemic agents, while at the same time they can serve as the starting point for their exploitation for antidiabetic usage and the development of novel biofunctional foods.