Acute hyperglycemia (HG) exacerbates reperfusion injury and aggravates tissue plasminogen activator (tPA)-induced hemorrhagic transformation (HT). Previous experimental hyperglycemic stroke studies employed very high blood glucose levels and exclusively used suture occlusion model to induce ischemia. Only few studies evaluated HG in embolic stroke and mostly involving the use of 10-fold higher dose of tPA than that is used in patients. However, the interaction between acute HG and low (human) dose tPA in different experimental models of stroke has never been reported. We first tested the impact of the severity of acute HG on stroke outcome. Building upon our findings, we then compared the impact of mild acute HG on neurovascular injury in rats subjected to suture or thromboembolic occlusion with and without low dose tPA. We assessed cerebral blood flow, neurobehavioral outcomes, infarction, hemorrhage, and edema. tPA did not change the infarct size in either control or hyperglycemic animals when compared to no tPA groups. HG increased HT and worsened functional outcomes in both suture and embolic occlusion models. The combination of HG and tPA exacerbated the vascular injury and worsened the neurological deficits more than each individual treatment in both models. Our findings show that the interaction between HG and even low dose tPA has detrimental effects on the cerebrovasculature and functional outcomes independent of the method of reperfusion.