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Introduction: Stroke is one of the leading causes of death and disability worldwide. Propolis, a polyphenol-rich resinous product processed by honeybees from a variety of plant sources, has a set of biological activities. We investigated the neuroprotective effect of Iranian brown propolis (IBP) in a mouse model of permanent middle cerebral artery occlusion (MCAO). Methods: Experimentally, water extracts of propolis (WEPs) were obtained from Kerman (KeWEP) and Khorasan Razavi (KhWEP) provinces, Iran. The chemical characterization and total polyphenol content of WEPs were determined using the Folin–Ciocalteu assay and gas chromatography-mass spectrometry (GC-MS). Animals were divided into eight experimental groups including: sham, control, and three groups each of which KeWEP- and KhWEP-treated mice. The drugs were administered at doses of 30, 100 and 200 mg/kg, intraperitoneally (IP), during four different time points. Infarct volume and brain edema were measured at 48 h. Behavioral tests were evaluated at 4, 24 and 48-hour post stroke. Results: The total polyphenol content was 1100 and 1400 mg/L in KhWEP and KeWEP respectively. Compared to the control group, the doses of 100 and 200 mg/kg in both samples decreased infarct volume. Brain edema was also reduced in all treatment groups. The dose of 200 mg/kg in both samples and 100 mg/kg in the KeWEP-treated group significantly increased grasping ability. Sensory-motor function was improved in all groups, too. Conclusion: These results suggest that IBP may reduce ischemic brain injury by its neuroprotective effect on focal cerebral ischemia.