Objective: To investigate whether pre-administration of butylphthalide can alleviate ischemic brain injury through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in a mouse model of acute cerebral infarction. Methods: Nrf2^-/- homozygous and Nrf2^+/+ wild-type mice were randomly divided into 3 groups: control group (C), low-dose butylphthalide group (20mg/kg) and high-dose butylphthalide group (60mg/kg), 6 mice in each group. Butylphthalide was dissolved in vegetable oil at 30 mg/ml. The low-dose group was given 20 mg/kg body weight by gavage, the high-dose group was given 60 mg/kg body weight by gavage, and the control group was given the same dose of vegetable oil by gavage. Once daily for 4 weeks. The mouse focal cerebral infarction model (dMCAO) was established by electrocoagulation at the end of 4 weeks. After 3 days and 10 days of the cerebral infarction model, the neurological function of the mice was evaluated by Longa score. The cerebral infarction volume of mice was detected by TTC, and the protein expression levels of Nrf2, NQO-1 and HO-1 in mouse brain tissue were detected by Western blot and immunofluorescence techniques. Results: Compared with Nrf2 wild-type mice, Nrf2 knockout mice showed greater weight loss after dMCAO, higher modified Longa score, larger cerebral infarct volume, and Nrf2 and downstream HO- 1 and NQO-1 protein expression levels were significantly up-regulated. In Nrf2^+/+ wild-type mice, the modified Longa score of the high-dose butylphthalide group (60^+/+) was lower than that of the non-dose butylphthalide mice (C^+/+), the volume of cerebral infarction was reduced, and the high-dose butylbenzene Phthalophthalene (NBP) has a preventive effect on high-risk ischemic stroke brain injury; in mice knocked out of the Nrf2 gene, the protective effect of high-dose NBP on the level of cerebral infarction and neurological function in mice disappeared, and the downstream heme oxygenation could not be induced. Up-regulation of protein expression levels of enzyme (HO-1) and NAD(P)H quinidone oxidoreductase 1 (NQO-1). Conclusion: Pre-administration of butylphthalide may have a certain protective effect on the brain injury of high-risk ischemic stroke, which can protect the neuromotor balance function and reduce the infarct size in ischemic stroke mice. Knockout of Nrf2 aggravated the brain injury in mice with ischemic cerebral infarction. High-dose butylphthalide can up-regulate the expression of Nrf2 and its downstream NQO-1 and HO-1 proteins in the brain tissue of mice, exerting its physiological function.