The present study aimed to investigate the potential protective effects of Astragaloside IV (AS-IV) against ethanol-induced gastric mucosal injury in rats. The animals were divided into 7 groups and pretreated with vehicle, various doses of AS-IV (1,2 and 4 mg/kg, i.p.) or omeprazole (40 mg/kg), 75 min later, the gastric mucosal injury was induced by oral administration of ethanol. One hour after ethanol ingestion, the rats were euthanized and gastric tissues were collected to biochemical analyze. Myeloperoxidase (WO), tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 10 (IL-10), nuclear factor kappa B (NF-kappa B) p65 protein, TNF receptor-associated factor 2 (TRAF2) and nuclear NF-kappa B (nNF-kappa B) proteins were estimated by enzyme-linked immunosorbent assay or western blot analysis. The gastric mucosal lesions were assessed by macroscopic and histopathological examinations. The results showed pretreatment with AS-IV attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of injury scores, histopathologic aberrations and leukocyte invasion. These actions were analogous to the reference omeprazole. AS-IV suppressed gastric inflammation by curbing of MPO, TNF-alpha levels along with NF-kappa B p65 and TRAF2 expression. It also augmented the anti-inflammatory IL-10 levels. Meanwhile, AS-IV could inhibit NF-kappa B transcription by inhibiting the expression of NF-kappa B p65 and increasing the expression of nNF-kappa B. It seems that AS-IV as an anti-inflammatory agent may have a protective effect against ethanol-induced mucosal injury by inhibition of neutrophil infiltration and reducing the expression of NF-kappa B p65, TRAF2 and inflammatory cytokines via regulating TNF-alpha/NF-kappa B signal pathway in gastric tissue.