OBJECTIVE: To investigate the anti-apoptosis and anti-ferroptosis effects of dl-3-n-butylphthalide (dl-NBP) on cerebral ischemia-reperfusion injury (CIRI) in rats, and the potential involvement of cysteine-X-cysteine chemokine receptor 4 (CXCR4). METHODS: The differentially expressed genes between healthy people and stroke patients were screened by GEO database. A transient middle cerebral artery occlusion rat model was used to induce CIRI in vivo. Rats were randomly divided into sham group, tMCAO group, and dl-NBP + tMCAO group. The therapeutic effect of dl-NBP in vivo and its effect on apoptosis and ferroptosis in brain tissues were evaluated. An in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was established to simulate CIRI in cultured PC12 cells, and the effects of dl-NBP on apoptosis and ferroptosis were examined. In this model, CXCR4 expression was assessed by western blotting and its involvement in dl-NBP-mediated protection assessed by inhibition with AMD3100. RESULTS: In the stroke-related GSE22255 and GSE66724 datasets, a total of six genes with increased co-expression were found, including CXCR4. Dl-NBP treatment significantly reduced both the volume of cerebral infarction and the degree of cerebral edema, and improved neurological function in rats. dl-NBP reduced the degree of apoptosis and ferroptosis and alleviated CIRI both in vivo and in vitro. The pro-survival effects of dl-NBP were significantly reversed after CXCR4 inhibition with AMD3100. CONCLUSION: Dl-NBP has anti-apoptotic and anti-ferroptotic effects on CIRI both in vivo and in vitro, and this effect is mediated by CXCR4.