It has been reported that ischemic postconditioning (PC) changes the reperfusion pattern in permanent or transient models of stroke and confers neuroprotection. However, the effects of PC and subsequent use of tissue plasminogen activator (tPA) for the treatment of embolic stroke have not yet been investigated. Rats were subjected to stroke by injection of a preformed clot into the middle cerebral artery and randomly assigned to vehicle (saline 0.1 ml/100 g), tPA (3 mg/kg), PC only or PC+tPA (3 mg/kg). tPA was injected at 6 h after embolic stroke and PC was conducted at 6.5 h after ischemia by using five cycles of a 10 s occlusion and 30 s of reopening of the bilateral common carotid arteries. Cerebral blood flow (CBF) was monitored for 60 min from the time of tPA injection. Infarct size, blood brain barrier disruption, edema, neurological deficits, reactive oxygen species and apoptosis were measured 2 days later. PC decreased infarct volume, but PC+tPA was more neuroprotective than PC alone. While tPA alone dramatically increased CBF, conducting PC caused a gradual increase in CBF. A combination of PC+tPA reduced BBB leakage, brain edema, apoptosis and reactive oxygen species levels. Furthermore, a combination of PC+tPA improved neurological functions at 48 h after the induced stroke. In conclusion, PC hampered malignant hyperemia after reperfusion with tPA and extended its therapeutic window up to 6 h. Compared to PC alone, combination of thrombolysis and PC showed a better neuroprotection.