Abstract： Objective： To observe the clinical effect of Jieyu Anshen Decoction combined with Fluoxetine Hydrochloride on adolescents with mild to moderate depression with liver depression and spleen deficiency syndrome. Methods：A total of 90 cases of adolescents with mild to moderate depression with liver depression and spleen deficiency syndrome were selected and divided into the control group and the treatment group according to the random number table method，with 45 cases in each group. The control group was treated with Fluoxetine Hydrochloride Capsules， and the treatment group was additionally treated with Jieyu Anshen Decoction based on the treatment of the control group. Both groups were treated for 4 weeks. The clinical effects， traditional Chinese medicine (TCM) syndrome scores， Hamilton Depression Scale (HAMD) scores，and the levels of serum monoamine neurotransmitters and inflammatory factors were compared between the two groups. Results：After 4 weeks of treatment，the total effective rate was 91.11% in the treatment group， higher than that of 73.33% in the control group (P＜0.05). The TCM syndrome scores in the two groups were decreased when compared with those before treatment (P＜ 0.05) ， and which was lower in the treatment group than that in the control group (P ＜ 0.05). After 2 and 4 weeks of treatment，HAMD scores in the two groups were decreased when compared with those before treatment (P＜0.05). After 2 weeks of treatment，there was no significant difference being found in the comparison of HAMD scores between the two groups (P＞0.05). After 4 weeks of treatment，HAMD score in the treatment group was lower than that in the control group (P＜0.05). After 4 weeks of treatment， the levels of 5-hydroxytryptamine (5-HT) in serum in the two groups were increased when compared with those before treatment (P＜0.05)，and the levels of norepinephrine (NE)，interleukin-2 (IL-2)，interleukin- 6 (IL-6)，and tumor necrosis factor-α (TNF-α) in serum were decreased when compared with those before treatment (P＜0.05). The level of serum 5-HT in the treatment group was higher than that in the control group (P＜0.05)， and the levels of NE， IL-2， IL-6， and TNF - α in serum were lower than those in the control group (P＜0.05). Conclusion：Jieyu Anshen Decoction combined with Fluoxetine Hydrochloride for adolescents with mild to moderate depression with liver depression and spleen deficiency syndrome has a significant curative effect， which can reduce clinical symptoms and improve depressive state. Its action mechanism can be related to regulating the levels of monoamine neurotransmitters and inflammatory factors.