The increase in the incidence of hyperglycemia and diabetes poses the challenge to search cost-effective natural inhibitors of starch digestion enzymes. Among natural compounds, phenolics have been considered as promising candidates. The aims of this study were: a) to investigate if winemaking byproducts are effective as inhibitors of the intestinal brush border alpha-glucosidase and the pancreatic alpha-amylase in vitro; b) to calculate an efficacy index for their phenolic pool, despite their variability due to grape cultivar and winemaking process; c) to compare winemaking byproducts’ efficacy with those of other plants. Winemaking by-products were characterized for the contents of total phenolics, flavanols, flavonols and anthocyanins, as well as the inhibitory activity towards the intestinal brush border alpha-glucosidase and pancreatic alpha-amylase. The inhibition towards alpha-glucosidase resulted to be on average 2.29 and 4.89 µg acarbose equivalents/µg total phenolics (µg Ac eq/µg GAE) for white and red grape skins, respec-tively. The inhibition towards alpha-amylase was 0.5 and 1.6 µg Ac eq/µg GAE for white and red grape skins, respectively. The inhibitory activity of the phenolic pool of red grape skins was higher than those of isolated phenolic compounds, probably due to synergistic effects among compounds. Hence, bioactive phenolic fractions could be produced with the focus on functionality rather than purity, in line with the principles of sustainable processing. A correlation was observed between the total phenolic contents of red grape skins and their inhibitory effectiveness, which is useful to standardize the efficacy of phenolic extracts. Compared to other plants reported in the literature red grape skins resulted to be cost-effective sources of starch digestion enzyme inhibitors.