This study was designed to investigate the protective effect and potential mechanism of oxycodone on intestinal ischemia-reperfusion (IIRI) injury in rats. Fifty adult male SD rats were randomly divided into sham-operated (SO), IIRI, and low-, middle-, and high-dose oxycodone groups, 10 rats in each group. The low-, middle-, and high-dose oxycodone groups received the tail vein injection of 0.125, 0.25, and 0.5 mg/kg oxycodone, respectively. After 15 min, the IIRI model (clamping superior mesenteric artery for 1 h, followed by reperfusion for 2 h) was established in IIRI, and low-, middle-, and high-dose oxycodone groups. At the end of reperfusion, compared with IIRI group, in middle- and high-dose oxycodone group the intestinal mucosal Chiu's score was significantly decreased, the serum tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta levels were significantly decreased, the intestinal tissue myeloperoxidase and malondialdehyde levels were significantly decreased, the intestinal tissue superoxide dismutase and glutathione peroxidase levels were significantly increased, and the intestinal tissue Beclin-1 expression level and LC3-II/LC3-I ratio were significantly increased. In summary, our study demonstrates that the oxycodone pretreatment can alleviate the IIRI in rats by decreasing inflammatory response, reducing oxidative stress and promoting intestinal tissue autophagy.