Buyang Huanwu Decoction fraction extracted from Buyang Huanwu Decoction contains saponins of Astragalus, total paeony glycoside and safflower flavones. The aim of this study was to demonstrate the neuroprotective effect and mechanism of Buyang Huanwu Decoction fraction on ischemic injury both in vivo and in vitro. In vivo experiments showed that 50-200 mg/kg Buyang Huanwu Decoction fraction reduced infarct volume and pathological injury in ischemia/reperfusion rats, markedly inhibited expression of nuclear factor-κB and tumor necrosis factor-α and promoted nestin protein expression in brain tissue. Buyang Huanwu Decoction fraction (200 mg/kg) exhibited significant effects, which were similar to those of 100 mg/kg Ginkgo biloba extract. In vitro experimental results demonstrated that 10-100 mg/L Buyang Huanwu Decoction fraction significantly improved cell viability, decreased the release of lactate dehydrogenase and malondialdehyde levels, and inhibited the rate of apoptosis in HT22 cells following oxygen-glucose deprivation. Buyang Huanwu Decoction fraction (100 mg/L) exhibited significant effects, which were similar to those of 100 mg/L Ginkgo biloba extract. These findings suggest that Buyang Huanwu Decoction fraction may represent a novel, protective strategy against cerebral ischemia/reperfusion injury in rats and oxygen-glucose deprivation-induced damage in HT22 cells in vitro by attenuating the inflammatory response and cellular apoptosis.