Abstract Compound FLZ is a synthetic novel derivate of natural squamosamide, which has potent neuroprotective effects based on our previous study. We are now aiming to investigate the effects of FLZ on cerebral blood flow (CBF), infarct volume, neurological function, heat shock protein 70 (Hsp70), and Hsp27 expression in transient focal ischemia. For this goal, an animal model of middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion was used, and animals received low or high doses of FLZ (150 or 300mg/kg), orally 10min after MCAO onset. The results show that the infarct volume was 32.7% for the vehicle control group, and reduced to 17.6 and 12.8% for the low and high dose FLZ-treated groups, respectively. FLZ treatment also significantly improved the neurobehavioral score from 2.6 in the vehicle control group to 1.0 and 0.9 in the low and high dose groups, respectively. Further, FLZ significantly induced Hsp27 over-expression and reduced over-expression of HSP70, a sensitive marker of acute ischemia, in ipsilateral cortex by a dose-dependent manner. In addition, CBF was quantified using laser-Doppler flowmetry. During ischemia, regional CBF (rCBF) was improved from approximately 30% to over 50% of the baseline and the reperfusion-induced hyperemia was reduced in both FLZ dosage groups. Particularly, high dose FLZ reduced rCBF during hyperemia by 30%. In conclusion, FLZ (150 and 300mg/kg) can significantly reduce the infarct volume and improve neurobehavioral deficits in a rat MCAO model, most likely through improving CBF in the penumbra and enhancing Hsp27 expression.