Objective To investigate the effects of centipede extract on the histomorphology and neuroglobin (NGB) expression in the ischemic penumbra after focal cerebral ischemia- reperfusion injury in rats and to explore the mechanism of action of centipede in preventing and treating cerebral ischemia at histopathological and molecular levels. Methods Rats were randomly divided into sham- operation group, model group,high- , middle- , and low- dose centipede extract groups, and qi- tonifying and blood- activating prescription (QBP) group. A rat model of focal cerebral ischemia- reperfusion of the middle cerebral artery was established by suture method. After modeling, these groups received respective treatments by gavage for 14 consecutive days. The histomorphology of ischemic penumbra in the frontal and parietal cortex was observed under a light microscope; the expression of NGB was measured by immunohistochemistry. Results The model group showed remarkable cerebral edema and neuronal necrosis in the ischemic penumbra in the frontal and parietal cortex. By contrast, the high- , middle- , and low- dose centipede extract groups and QBP group had 〖JP2〗significantly reduced pathological changes in the ischemic penumbra in the frontal and parietal cortex. There were no significant differences in the positive expression area and mean optical density of NGB between the sham- operation group and model group (P>0.05). The positive expression area and mean optical density of NGB showed significant differences between the model group and the high- , middle- , and low- dose centipede extract groups (P<0.05), and the difference was most significant between the model group and the high- dose centipede extract group. The positive expression area and mean optical density of NGB also showed significant differences between the QBP group and the high- , middle- , and low- dose centipede extract groups (P<0.05), but the two indices showed no significant differences between the QBP group and the high- dose centipede extract group (P>0.05). Conclusion Centipede extract can reduce the focal cerebral ischemia- reperfusion injury in rats by up- regulating the expression of NGB in the ischemic penumbra in a significant dose- dependent manner, and high- dose centipede extract has comparable efficacy to QBP.