Abstract: Objective: This study aimed to investigate the protective effect and underlying mechanism of a combined glutamine and curcumin formulation on ethanol-induced gastric mucosal damage in rats. Method: A total of fifty SPF-grade healthy SD male rats were randomly partitioned into five groups: A normal group, a model control group, a cimetidine group, a high-dose treatment group, and a low-dose treatment group. After a period of 30 days marked by oral gavage administration, all groups, with the exception of the normal group, were euthanized post anhydrous ethanol-induced modeling. The histopathological alterations in the gastric mucosa were observed via hematoxylin & eosin (H&E) staining. Furthermore, serum levels of malondialdehyde (MDA), nitric oxide (NO), and glutathione peroxidase (GSH-PX) were ascertained using a specific reagent kit. Concurrently, the concentration of prostaglandin E₂ (PGE₂) within the tissue and the expression levels of heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase (NQO1), the antioxidant-related nuclear factor-E2-related factor 2 (Nrf2) gene, and glycogen synthase kinase-3β (GSK-3β) were evaluated. Results: In the cimetidine and high-dose treatment groups, the incidence of gastric mucosal bleeding and other forms of injury were noticeably mitigated (P<0.05) compared to the model control group, with the high-dose treatment group demonstrating a more pronounced effect. Moreover, the model control group exhibited a significant elevation in MDA content and GSH-P_X activity and a concurrent decline in NO and PGE₂ levels (P<0.05). The expression of antioxidant-related genes, namely, HO-1, NQO1, and Nrf2, was significantly suppressed (P<0.05), whereas GSK-3β expression was markedly increased. In contrast, in comparison to the model control group, the cimetidine and high-dose treatment groups manifested a significant reduction in MDA content and GSH-PX activity, while NO and PGE₂ levels notably increased (P<0.05). The expression of the antioxidant-related genes HO-1, NQO1, and Nrf2 was significantly returned to normal (P<0.05), and GSK-3β expression was suppressed (P<0.05). Conclusion: The combined formulation appears to exert an inhibitory effect on ethanol-induced acute gastric mucosal damage. This effect is hypothesized to be associated with the Keap1-Nrf2-ARE oxidative stress signaling pathway.