Objective To investigate the effects of Wuling Capsule on PI3K/Akt/mTOR pathway and neurotransmitters in hippocampus of post-stroke depression rats.Methods The 48 healthy SD rats were randomly divided into control group, model group, low-dose group and high-dose group with 12 rats in each group. The modified Zea Longa method was used to establish the model of middle cerebral artery occlusion (MCAO) in rats, followed by subcutaneous injection of reserpine to prepare post-stroke depression model. The control group and model group were given the same dose of double distilled water by gavage. The low-dose group was given 40 mg Wuling Capsule since the second day after successful modeling, while the high-dose group was given 80 mg Wuling Capsule since the second day after successful modeling. Rats in each group were gavaged once a day for 21 days. The protein expression of PI3K, p-Akt and p-mTOR in hippocampus was determined by Western blotting, and the contents of NE, DA and 5-HT in hippocampus were determined by HPLC.Results The Zea Longa scores of rats in the model group, low-dose group, and high-dose group were all higher than those in the control group (P < 0.05); the protein expressions of PI3K, p-Akt and p-mTOR in hippocampus were all lower than those in the control group (P < 0.05); and the contents of NE, DA and 5-HT in hippocampus were lower than those in the control group (P < 0.05). Besides, the Zea Longa scores of rats in the low-dose and high-dose groups were lower than those in the model group (P < 0.05); the protein expressions of PI3K, p-Akt and p-mTOR were higher than those in the model group (P < 0.05); and the contents of NE, DA and 5-HT in hippocampus were higher than those in the model group (P < 0.05).Conclusions Wuling Capsule can improve the behavior of post-stroke depression rats, and regulate PI3K/Akt/mTOR pathway and neurotransmitter level.