Objective To explore the effect of FTY720 on the behavior and monoamine neurotransmitters of post- stroke depression rats. Methods Fifty male SD rats were randomly divided into sham operation, stroke, PSD, FLU, and FLU+FTY720 groups(n= 10 each). The middle cerebral artery thread embolization method was used to establish a focal cerebral ischemia rat model. The PSD rat model was established by combining chronic unpredictable mild stress and isolation method . At 1, 8, 15, 22, and 29 days of stimulation, the behavioral indexes of rats in each group were evaluated. The rats were sacrificed on day 29 and the content of monoamine neurotransmitters and expression of the rate-limiting enzyme of monoamine neurotransmitter synthesis in the hippocampus of rats in each group were analyzed. Results Compared with sham operation and stroke groups, the open field test score and volume ratio of sucrose water consumption of the PSD group were significantly reduced at the same time points ( P< 0. 05). Levels of 5-HT, NE, and DA were significantly reduced in the hippocampus ( P< 0. 05 ). Expression of TPH2 and TH mRNAs was decreased in the hippocampus(P< 0. 05). Compared with the PSD group, the open field test score and volume ratio of sucrose water consumption of FLU and FLU+FTY720 groups were increased at the same time points(P<0. 05). Levels of 5-HT, NE, and DA were increased in the hippocampus(P<0. 05). Expression of TPH2 and TH mRNAs was upregulated in hippocampus(P<0. 05). Conclusions FTY720 improves the depression-like behavior of PSD rats and its effect is related to increasing the levels of monoamine neurotransmitters.