Melagatran is a potent direct thrombin inhibitor and it is an effective agent in the prevention of stroke in patients with atrial fibrillation (AF); however, there are no data about its actions in the treatment of acute ischemic stroke. In the present study, we evaluated the neuroprotective actions of melagatran using an embolic model of stroke in rats. We first examined protective effects at increasing doses of melagatran. Then, we examined the effects of melagatran administered at different time points following middle cerebral artery (MCA) occlusion. We also evaluated the effects of combination therapy with melagatran and tissue plasminogen activator (tPA) in this model. Finally, we examined if melagatran can improve compromised microcirculation in the ischemic injured brain. The medication alone or in combination with tPA was well tolerated. Melagatran reduced ischemic brain injury in a dose-response manner, and also in a time dependent manner. Combination treatment of melagatran and tPA was superior to either treatment alone. There was no significant increase in symptomatic or asymptomatic hemorrhages in the treated animals. Melagatran treatment also reduced perfusion deficits in the ischemic injured brain. The present study is the first report on the usefulness of melagatran in embolic ischemic stroke. Our research shows that melagatran is an effective agent in the treatment of ischemic brain injury. The protective effects of this medication are likely due to its actions in enhancing thrombus dissolution and preventing formation of microthrombosis in the ischemic injured brain. Finally, the combination with melagatran and tPA appears safe and superior to each treatment offered alone.