Thrombosis and accompanying inflammation have been reported to affect the severity of ischemia-reperfusion (I/R) injury. Tissue plasminogen activator (tPA) initiates fibrinolysis through the conversion of plasminogen to plasmin. Increased fibrinolysis has been shown to lessen the severity of I/R injury in various organs. This study aimed to investigate the effects of tPA on intestinal I/R injury. Twelve Wistar albino rats were randomly divided into two groups (a sham group, and a tPA group). The superior mesenteric artery was occluded by clamping it for 45 minutes. Then, following the clamp removal, serum physiologic was given to the sham group, and tPA was given to the tPA group, and then all the small intestine specimens were examined by a pathologist. The specimens were scored according to the Park/Chiu classification and immunohistochemical staining of anti-IL-6 and TNF-alpha. The median of the scores was 4 (3-6) in the sham group and 2.25 (2-3) in the tPA group. The difference between the median scores in the sham and tPA groups was statistically significant (P=0.009). The mean anti-IL-6 and anti-TNF-alpha-stained cell counts were significantly different when the sham group and the tPA group were compared (P=0.004 and P=0.004). It was determined that tPA has an essential role in lessening the severity of intestinal I/R injury and it is suggested that further studies should be conducted on the effects of fibrinolytic management on intestinal I/R injury.