Abstract Oleoylethanolamide (OEA) is a high-affinity agonist of peroxisome proliferator-activated receptor α (PPARα) which may act as an endogenous neuroprotective factor. However, it is not clear whether orally administered OEA is effective against ischemic brain injury. In our study, transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 90 min followed by reperfusion. To evaluate its preventive effects, OEA (10, 20 or 40mg/kg, ig) was administered for 3 days before ischemia. To evaluate its therapeutic effects, OEA (40mg/kg, ig) was administered at 0.5 or 1h before reperfusion or at 0 or 1h after reperfusion. In some experiments, the PPARα antagonist MK886 (10mg/kg, ig) was administered 0.5h before OEA. Neurological deficit score, infarct volume and brain edema degree were determined at 24h after reperfusion. Blood–brain barrier (BBB) disruption was evaluated by Evans blue (EB) leakage at 6h after reperfusion. Real-time RT-PCR and western blot were performed to detect PPARα mRNA and protein expression. Oral OEA pretreatment improved neurological dysfunction reduced infarct volume and alleviated brain edema in a dose-dependent manner; the most effective dose was 40mg/kg. The therapeutic time is within 1h after reperfusion. OEA also increased PPARα mRNA and protein expression in the ischemic brain. The PPARα antagonist MK886 abolished the protective effects of OEA. In conclusion, our results indicate that orally administered OEA protects against acute cerebral ischemic injury in mice, at least in part by activating PPARα.