Background: Intestinal tissue is highly susceptible to ischemia/reperfusion (I/R) injury in many hazardous health conditions. The anti-inflammatory and antioxidant glycoprotein fetuin-A showed efficacy in cerebral ischemic injury, however its protective role against intestinal I/R remains elusive. Objective: This study investigated the protective role of fetuin-A supplementation against intestinal structural changes and dysfunction in a rat model of intestinal I/R. Materials and methods: We equally divided 72 male rats into control, sham, I/R, and fetuin-A-pretreated I/R (100 mg/kg/day fetuin-A intraperitoneally for 3 days prior to surgery and a fourth dose 1h prior to the experiment) groups. After 2 h of reperfusion, the jejunum was dissected and examined for spontaneous contractility. A jejunal homogenate was used to assess inflammatory and oxidative stress enzymes. Staining of histological sections was carried out with hematoxylin, eosin and Masson’s trichrome stain for evaluation. Immunohistochemistry was performed to detect autophagy proteins beclin-1, LC3, and p62. Results: This study found that fetuin-A significantly improved I/R-induced mucosal injury by reducing the percentage of areas of collagen deposition, increasing the amplitude of spontaneous contraction, decreasing inflammation and oxidative stress, and up regulating p62 expression, which was accompanied by beclin-1 and LC3 down regulation. Conclusion: Our findings suggest that fetuin-A treatment can prevent I/R-induced jejunal structural and functional changes by increasing antioxidant activity and regulating autophagy disturbances observed in the I/R rat model. Furthermore, fetuin-A may provide a protective influence against intestinal I/R complications. Key words: Ischemia/reperfusion; Fetuin-A; Autophagy; Inflammation; Jejunum; Antioxidant.