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Hyperglycemia is a significant risk factor in metabolic syndrome, contributing to the development of cardiovascular diseases and diabetes mellitus. Hyperglycemia increases ROS (reactive oxygen species) production via glucose oxidation and protein glycosylation, leading to cell damage. Our previous studies have highlighted the antioxidant properties of wine pomace products (wWPPs), a co-product of winemaking, and their ability to modulate oxidative stress. The objective of this study was to evaluate the protective effect of wWPPs against oxidative stress in hyperglycemic Caco-2 cells. They were treated with 1.5 μg GAE/mL of wWPP bioaccessible fractions, obtained from gastrointestinal digestion (WPGI) and colonic fermentation (WPF), under normoglycemic or hyperglycemic (35 mM glucose) conditions. After 24 h of treatment, cell viability, oxidative stress biomarkers and the expression of transcription factors and enzymes involved in cellular oxidation balance were evaluated. Hyperglycemia induced a 30% reduction in cell viability, which was restored to normoglycemic levels by WPF treatment. The bioaccessible fractions were able to counteract hyperglycemia-induced oxidative stress in intestinal cells, as evidenced by significant decreases in carbonyl groups and MDA levels (10 and 40%, respectively). Furthermore, hyperglycemia-induced NF-κB overexpression was also significantly reduced by WPGI and WPF pre-treatment (between 15 and 53%), modulating the redox activity. In conclusion, the bioaccessible fractions of wWPP, particularly WPF, demonstrated significant potential in mitigating hyperglycemia-induced oxidative stress and enhancing cell viability in Caco-2 cells.