The present study was aimed to investigate the effect of wheat oligopeptide and glutamine on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastrointestinal mucosa damage in rats. Method: 70 SD rats were randomly divided into control group, damage group, low, medium and high doses of the wheat peptide group (the doses were 20, 100 and 500 mg/(kg·d), respectively), wheat gluten group and glutamine group (the doses were both 20 mg/(kg·d)). The rats were administered once a day for continuous 30 days. Before sacrificing, NSAIDs were infused into the digestive tract twice. Serum, stomach and small intestine mucosa samples were collected to observe the changes of the indicators of serum cytokine, pathological section of stomach and small intestine, enzyme activity of small intestinal antioxidase and opioid receptor mRNA expression. Results: Wheat oligopeptides administration reduced gastrointestinal mucosa damage, and significantly decreased the level of TNF-alpha in serum. Oxidative stress was significantly increased after NSAID infusion and was reduced by wheat oligopeptides. Wheat oligopeptides increased glutathion peroxidase (GSH-Px) activity in mucous membrane of small intestine. Mu opioid receptor mRNA expression decreased more significantly in wheat oligopeptides treated rats than in the model control group. Conclusion: Non-steroidal anti-inflammatory drugs can induce small intestinal damage in rats and wheat oligopeptides administration may be an effective tool for protecting gastrointestinal tissue against NSAID-induced gastrointestinal damage and oxidative stress. The effect of low doses of the wheat peptide group was the strongest, and stronger than that of glutamine group.