Objective: To investigate the effects of Ganmai Dazao Tang on behavior and monoamine neurotransmitters in rats with depression, and to explore its potential mechanism from synaptic structure. Methods: Sixty SD rats were randomly divided into 5 groups: normal control group, model group, fluoxetine group (10.8 mg/kg), Ganmai Dazao Tang high and low dose group (9.72, 4.86 g/kg), 12 rats in each group. Except the control group, the rats in the other groups were all chronically unpredictable mild stress (CUMS) to establish a depression model, and were treated by intragastric administration for 21 days. The depression-like behaviors of rats were evaluated by sucrose consumption test and open field test. The contents of serotonin (5-HT) and norepinephrine (NE) in hippocampus were detected by ELISA. The synaptic damage of neurons was observed by Golgi staining. The synaptic structure protein expression levels of MAP-2 and GAP-43 of hippocampus were detected by Immunohistochemistry and Western blot. Results: Compared with control group, the sucrose preference and autonomic activity scores of the depression model rats were decreased significantly (P<0.01), the levels of 5-HT and NE in hippocampus were decreased significantly (P<0.01), and the dendritic spines were absent, and the expressions of MAP-2 and GAP-43 were down-regulated significantly (P<0.01). After treated with Ganmai Dazao Tang, the depression-like behavior of the model rats was significantly relieved (P<0.01), and the levels of 5-HT and NE were increased (P< 0.05). Dendritic spine density, length and branching were increased, the expressions of MAP-2 and GAP-43 were increased (P< 0.01). Conclusion: Ganmai Dazao Tang can improve the depression-like behavior of depression model rats and increase the monoamine neurotransmitter content in hippocampus, which may be related to up-regulation of synaptic structural proteins and relief of synaptic damage in neurons.