It is well-known that patients with diabetes mellitus have worse clinical outcomes following acute ischemic stroke. The intensifying effects of diabetes on ischemic brain injury have been shown to be mostly due to hyperglycemia, rather than the lack of insulin direct effects on brain. It is also well-approved that vanadium compounds have insulin-like and anti-diabetic effects, and the present study was designed to compare the protective effects of diabetes treatment with vanadium or insulin on ischemic/reperfused brain injury. Male Sprague-Dawley rats were divided into 4 groups (n = 21). Two groups of streptozotocin-induced diabetic rats were treated with either vanadyl sulfate or insulin at proper doses to similarly attenuate hyperglycemia during 45 days, while there was no treatment in the control diabetic and non-diabetic sham groups. Thereafter, all treated and non-treated diabetic rats were subjected to 60-min of the right middle cerebral artery occlusion followed by 12-h reperfusion, and then their brains were removed for evaluating blood-brain barrier leakage, tissue swelling, infarct size and oxidant status in both hemispheres. Vanadium and insulin that equally reduced blood glucose and water intake had some differences in their antidiabetic effects of ameliorating weight loss and hypertension during 45-days treatment period. However, they caused similar decrements in levels of Evans blue dye extravastion, edema, infarct volume and malondialdehyde in ischemic/reperfused cerebral hemisphere. Therefore, it can be suggested that insulin and vanadium via their antiglycemic effect cause reduction in cerebral production of oxidants following acute focal ischemia/reperfusion, which attenuate BBB disruption and brain tissue injury.