Aim To investigate the effect of leonurine on the pathological changes of cerebral tissue in rats with ischemic stroke based on PI3K/AKT/NF-κB signaling pathway. Methods The rat model of ischemic stroke was established, and leonurine was administered continuously for 7 days. The neurological impairment score of each group was observed. The content of oxidative stress index was detected in rat brain tissue. The percentage of cerebral infarction area in rats was detected by TTC staining. HE staining was used to observe the pathological changes in cortex and hippocampus of rat brain. The expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducibal factor 1α (Hif-1α) in cerebral infarction cortex of rats were measured by real-time fluorescence quantitative polymerase chain reaction. Western blot was used to detect the protein expressions of phosphatidyl inositol-3-kinase (PI3K), serine-threonine protein kinase (AKT) and nuclear factor-κB (NF-kappa B) in brain tissue. Results Compared with the blank control group, the neurological impairment score, the contents of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS), mRNA expressions of VEGF and Hif-1α and protein expression of NF-κB were increased significantly, the contents of oxidized low density lipoprotein (ox-LDL) and superoxide dismutase (SOD), and protein expressions of AKT and PI3K were decreased significantly in rats of model control group; The differences had statistical significance (P＜0.01). Compared with the model control group, the neurological impairment score, the contents of NO and eNOS, mRNA expressions of VEGF and Hif-1α and protein expression of NF-κB were decreased significantly, the contents of ox-LDL and SOD, and protein expressions of AKT and PI3K were increased significantly in rats of positive control group and middle- and high-dose leonurine group; The differences had statistical significance (P＜0.01). Conclusions Leonurine has brain protective effect on rats with experimental brain injury. It can improve nerve injury after cerebral infarction, reduce the volume of cerebral infarction and reduce oxidative stress response. These effects may be achieved through PI3K/AKT/NF-κB signaling pathway.