The present study investigated the effect of the soybean polyphenol genistein on the stomach using a water immersion restraint (WIR) stress model. Male Wistar rats were administered 50 or 100 mg/kg/d of genistein for 2 wk or were not given any drug. Rats were subjected to WIR stress for 4 h. At the end of the WIR period, rats were sacrificed. Subsequently, rats underwent measurement of the ratio of the mucosal hemorrhagic erosion area to the whole stomach body area, myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, thiobarbituric acid reactive substances (TBARS) level, and proinflammatory cytokines (tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant (CINC)-1) levels in the gastric tissue. Furthermore, an isolated rat stomach infusion model was employed for the endocrinological investigation of the effect of genistein. The extracted stomach canal and the vascular system, which comprised the experimental model, were subjected to perfusion. After 20 min of perfusion, the perfusate from the portal vein was collected, and the concentrations of histamine, gastrin, and somatostatin in the perfusate were measured. Experiments demonstrated that genistein administration resulted in significant suppression of WIR stress-induced gastric mucosal injury and MPO activity. Further, genistein significantly elevated SOD activity and significantly suppressed the TBARS level, production of TNF-α and CINC-1, and secretion of gastrin, histamine, and somatostatin. These data suggest that genistein protected against gastric mucosal injury, likely via its ability to inhibit oxidation, inflammation, and secretion of gastrin and histamine.