Introduction: Free radicals and oxidative stress play a central role in the generation and development of acute gastric mucosal lesions (AGML). Traditional Chinese medicine has its unique effect in removing oxygen free radicals and reducing gastric mucosa injury. Polygonum hydropiper L is extensively used as a traditional Chinese herbal medicine for treating gastrointestinal diseases in China, the reports shows that it possess various pharmacological activities, especially antioxidant and anti-inflammatory properties. Objective: This study was to investigate the protective effect of extracts from Polygonum hydropiper on experimentally-induced AGML in mice. Methods: The AGML mice model was induced by ethanol, Glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and superoxide dismutase (SOD) were used to measure the antioxidant activity. The nitric monoxide (NO) and PGE2 contents were tested. Results: The findings demonstrated that the extracts enhanced the activities of antioxidative enzymes SOD and GSH-Px and decreased the level of MDA in the serum and gastric tissues. The higher-concentration extract (1.78 g kg-1) had higher antioxidative activities than the lower-concentration extract (0.89 g kg-1).Both extracts increased the production of PGE2and decreased the NO level in gastric tissues. In addition, oral administration of absolute ethanol to mice significantly produced extensive hemorrhagic lesions of gastric mucosa, whereas animals pretreated with extract or ranitidine significantly reduced the formation of gastric lesions compared to control group. The extract could decrease distinctly the acute gastric mucosal damage index compared to the model group. The high-dose extract treatment obviously reduced injuries in the gland region after administration of ethanol compared to the model group. Conclusion: The results obtained from this study showed that extracts from Polygonum hydropiper L exhibited significant protective effects against ethanol-induced AGML, and these are closely associated with antioxidant effect.