Aim To study effects of mangiferin on oxidative stress response and neuronal apoptosis in rats with hypoxic-ischemic brain injury by PI3K/Akt/mTOR pathway. Methods 144 neonatal SD rats were randomly divided into 6 groups:blank control group, model group, positive control group (Nimodipine), mangiferin low dose group (MAN-L), middle dose group (MAN-M) and high dose group (MAN-H). There were 24 rats in each group. The rat model of hypoxic-ischemic brain injury was made in all groups except the blank control group. After the model was made, the blank control group and the model group were given the same volume of normal saline, the positive control group was given nimodipine (0.4 mg/(kg·d)), and the mangiferin low, middle and high dose groups were given mangiferin 0,0, 200 mg/(kg·d) for 4 weeks. The neurological injury score of rats in each group was measured, the water content of brain tissue in each group was measured by dry and wet weight method, the pathomorphological changes of brain tissue were observed by hematoxylin-eosin (HE) staining, and the apoptosis of neurons in brain tissue of rats was detected by in situ apoptosis. The activities of superoxide dismutase (SOD), malondialdehyde (MDA), glutathion peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) in brain tissue were measured by biochemical detection, and the expression of PI3K/Akt/mTOR mRNA in rat brain tissue was measured by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR). The contents of caspase-3, Bcl-2, Bcl-xL, Bad and Bax proteins in brain tissue were detected by Western blot. Results The nerve injury score, water content of brain tissue, apoptosis number of nerve cells, MDA content, PI3K expression and caspase-3 content in the model group were significantly higher than those in the blank control group. The number of intact neurons, the contents of SOD, GSH-Px, T-AOC, Akt, mTOR and the contents of Bcl-2, Bcl-xL and Bad in the brain tissue of the model group were significantly lower than those of the blank control group. The nerve injury score, water content of brain tissue, apoptosis number of nerve cells, MDA content, PI3K expression and caspase-3 content in each drug group were significantly lower than those in the model group. The number of intact neurons, the contents of SOD, GSH-Px, T-AOC, Akt, mTOR and the contents of Bcl-2, Bcl-xL and Bad in the brain tissue of the drug group were significantly higher than those of the model group. Conclusion Mangiferin can enhance the neuroprotective effect, inhibit neuronal apoptosis and improve the survival rate of nerve cells by down-regulating the expression of caspase-3, up-regulating the expression of Bcl-2 and Bcl-xL, and enhancing the expression of PI3K/Akt/mTOR pathway.