Objective: Diabates mellitus, is a chronic metabolic disorder accompanied by an increase in oxidative stress. Ischemia-reperfusion injury is a cascade of events initiated by tissue ischemia. The cellular damage produced by reperfusion leads to an active inflammatory response. This study was performed to investigate the effect of picroside II on myocardial ischemia-reperfusion injury in rats with streptozotocin-induced diabetes. Methods: Animals were equally (n:6) divided for five groups as follows; Control (C), diabetes [D], diabetes+picroside II [DP], diabetes+I/R [DIR], and diabetes+I/R+ picroside II [DIRP]. In DIR group, a left anterior descending artery branch was occluded for 60 minutes, the reperfused for 120 minutes. In DIRP group, picroside II was administrated via 10 mg/kg intraperitoneal route 30 minutes before ligating the left anterior descending artery. At the end of the study, myocardial tissues were taken for total oxidant status and total antioxidant status level determinations. Results: Total oxidant status levels were significantly higher in DIR group, when compared with C, DP, and DIRP groups (p:0.001, p:0.019, and p:0.031, respectively). Total antioxidant status levels were significantly higher in DIR group, when compared with C, DP, and DIRP groups (p:0.006, p:0.024, and p:0.007, respectively). Conclusion: These results indicate that administration of picroside II may have protective effects against I/R injury.