Objective To investigate the protective effect of Taohong Siwu Decoction against reperfusion injury due to oxygen-glucose deprivation in brain microvascular endothelial cell (BMEC)-PC12 cell co-culture system. Methods Oxygen-glucose deprivation/recovery was performed to induce reperfusion injury due to oxygen-glucose deprivation in the BMEC-PC12 cell co-culture system. Flow cytometry was used to measure reactive oxygen species (ROS) in PC12 cells; enzyme-linked immunosorbent assay was used to measure the activities of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px); Western blot was used to measure the expression of Bcl-2, Bax, and hypoxia-inducible factor-1α (HIF-1α). Results Taohong Siwu Decoction promoted the viability of PC12 cells, inhibited cell apoptosis, reduced the production of ROS, and enhanced the activities of SOD and GSH-Px. In addition, it upregulated the expression of HIF-1α and Bcl-2 and downregulated the expression of Bax. Conclusion Taohong Siwu Decoction exerts a protective effect against cerebral ischemia/reperfusion injury via its antioxidant effect.