Aim To study the protective effect and molecular mechanism of losartan on cerebral ischemia reperfusion (IR) injury in rats. Methods 80 adult male SD rats were randomly divided into sham group, IR group, 2.5 mg/kg losartan group, 5.0 mg/kg losartan group and 5.0 mg/kg losartan＋LY group. 2.5 mg/kg losartan group, 5.0 mg/kg losartan group, 5.0 mg/kg losartan＋LY group were given losartan intragastrically for 14 days before modeling, and 5.0 mg/kg losartan＋LY group was given phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 intraventricular injection 30 minutes before modeling. The model of cerebral IR injury was established by thread embolism method. At 24 hours after reperfusion, the neurological deficit was evaluated, and the water content of brain tissue, cell apoptosis and expression of apoptosis related genes were measured. Results Compared with sham group, the brain water content, neurological deficit score, TUNEL positive rate and the levels of Bcl-2 associated X protein (Bax)/GAPDH, cytochrome C (CytC)/GAPDH, cleaved cysteinyl aspartate specific proteinase-3 (caspase-3)/pro-caspase-3 in brain tissue of rats in IR group were significantly increased, while the levels of B-cell lymphoma-2 (Bcl-2)/GAPDH, p-PI3K/PI3K, p-AKT/AKT in brain tissue were significantly decreased. Compared with IR group, the levels of the brain water content, neurological deficit score, TUNEL positive rate and the levels of Bax/GAPDH, CytC/GAPDH, cleaved-caspase-3/pro-caspase-3 in brain tissue of rats in 2.5 mg/kg losartan group, 5.0 mg/kg losartan group were significantly decreased, while the levels of Bcl-2/GAPDH, p-PI3K/PI3K, p-AKT/AKT in brain tissue were significantly increased. Compared with 5.0 mg/kg losartan group, the levels of the brain water content, neurological deficit score, TUNEL positive rate and the levels of Bax/GAPDH, CytC/GAPDH, cleaved-caspase-3/pro-caspase-3 in brain tissue of rats in 5.0 mg/kg losartan＋LY group were significantly increased, while the levels of Bcl-2/GAPDH, p-PI3K/PI3K, p-AKT/AKT in brain tissue were significantly decreased. Conclusion Losartan can alleviate cerebral IR injury by up-regulating PI3K/AKT pathway in rats.