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Introduction: The intestinal tract serves as an innate barrier, safeguarding the internal milieu from microorganisms and toxins. Various intestinal inflammatory diseases have a strong association with intestinal barrier dysfunction. The primary functional cells within the intestinal tract, intestinal epithelial cells (IECs) and their tight junctions (TJs), are crucial in preserving the integrity of this mechanical barrier. Resveratrol (Res), a plant-derived phenolic compound, exhibits a range of health-promoting benefits attributed to its anti-inflammatory properties. This study aims to examine Res's efficacy in bolstering IECs barrier function. Methods: Dextran sulfate sodium (DSS) was employed to induce barrier dysfunction in IECs. Inflammatory cytokines in supernatants (interleukin [IL]-6, IL-1β, tumor necrotic factor [TNF]-α, and IL-10) were quantified via enzymelinked immunosorbent assay (ELISA). Then we assessed monolayer integrity using transepithelial electrical resistance (TEER). TJ protein expression (zonula occludens [ZO]-1 and Occludin) in IECs was evaluated through immunofluorescence andWestern blot analysis. Network pharmacology helped identify the biological processes, signaling pathways, and key targets involved in Res's mitigation of DSS-induced IECs barrier dysfunction. The efficacy of the primary target was further corroborated using Western blot. Results: Res was shown to increase cell viability and IL-10 expression while reducing TNF-α, IL-6, and IL-1β levels, thus mitigating the inflammatory response. It enhanced TEER values and upregulated TJ protein expression (ZO-1 and Occludin). Network pharmacology revealed that Res potentially targets the NFE2L2 (nuclear factor erythroid-2-related factor 2, Nrf2), a vital antioxidant factor. Significantly, Res augmented Nrf2 and heme oxygenase 1 (HO-1) protein levels, counteracting oxidative stress in the IECs barrier dysfunction model. Conclusion: Overall, our findings suggested that Res ameliorated DSSinduced IECs barrier dysfunction by activating Nrf2/HO-1 pathway, showcasing significant therapeutic potential in the early stages of colitis. [ABSTRACT FROM AUTHOR]