OBJECTIVE : Hyperglycemia-mediated oxidative damage has been described as a major mechanism leading to pathologic changes associated with diabetic cardiomyopathy (DCM). Fisetin is a bioactive flavonol molecule found in many plants and possesses various biological activities. The present study investigated the protective effect of fisetin on diabetes-induced cardiac injury. METHODS : Diabetes was induced by streptozotocin (STZ) and both diabetic and control rats were treated with 2.5 mg/kg fisetin for six weeks. RESULTS : Diabetic rats exhibited hyperglycemia, and increased glycosylated hemoglobin and serum lipids accompanied with significant hypoinsulinism. In addition, diabetic rats showed several histological alterations in the myocardium, and significantly increased serum troponin I, creatine kinase-MB and lactate dehydrogenase. Oxidative stress, inflammation and apoptosis markers were increased, whereas antioxidant defenses were significantly reduced in the diabetic heart. Treatment with fisetin alleviated hyperglycemia, hyperlipidemia and heart function markers, and minimized histological alterations in the myocardium. Fisetin suppressed oxidative stress, prevented inflammation and apoptosis, and boosted antioxidant defenses in the heart of diabetic rats. CONCLUSIONS : Fisetin attenuated the development of DCM via amelioration of hyperglycemia/hyperlipidemia-mediated oxidative stress, inflammation and apoptosis. Therefore, it might be worth considering the therapeutic potential of fisetin for human DCM.