Abstract: Objective: To investigate the arsenic-induced small intestinal toxicity and the protective effect of grape skin extract (GSE) against arsenic toxicity. Methods: The small intestinal toxicity was induced by 10 mg/L arsenic via drinking water for 56 days, and was intervened with GSE (150 mg/kg bw and 300 mg/kg bw) by gavage every other day in mice. Small intestine tissue samples of mice were collected and observed by microscope. Glutathione (GSH), malondialdehyde (MDA) and H₂O₂ contents, as well as total superoxide dismutase (T-SOD) were determined by using commercial kits. qRT-PCR was used to detect expression levels of the tight junction genes and the inflammatory pathway IL-6/JAK2/STAT-3 genes. Results: The results showed that 56 days exposure to 10 mg/L arsenic via drinking water resulted in shortened and disordered intestinal villi, with large numbers of inflammatory cells infiltrating the mucosa propria and submucosa. GSH content and T-SOD activity decreased by 17.1% and 25.2%, while MDA and H₂O₂ contents increased by 68.8% and 54.3%, respectively (P<0.05) in the small intestinal tissue of arsenic-treated mice. The mRNA levels of IL-6, JAK2 and STAT-3 were upregulated in the small intestinal tissue of mice exposed to arsenic (P<0.05). Meanwhilethe mRNA levels of the ZO-1, ZO-2, occludin, claudin1 and claudin7 genes, which encode the key components of tight junction (TJ) complexes, were downregulated (P<0.05). However, the application of GSE (300 mg/kg bw) significantly alleviated the damage and inflammatory infiltration in small intestine. Compare to the As group, GSH content and T-SOD activity increased by 17.9% and 14.3%. MDA and H₂O₂ contents decreased by 33.8% and 25.4% (P<0.05). Arsenic-mediated gene expression in the IL-6/JAK2/STAT3 pathway was down-regulated (P<0.05). Moreover, the arsenic-induced down-regulation of TJ genes were markedly relieved in the As+GSE (300 mg/kg bw) group (P<0.05). The As+GSE (150 mg/kg bw) group had a certain alleviating effect on arsenic toxicity, but the difference had no statistical significance (P>0.05). Conclusion: The application of GSE provides significant protection against arsenic-induced small intestinal toxicity by attenuating the oxidative stress and inflammatory responses, and inhibiting the down-regulation of some functional genes.