Abstract： Objective： To observe the clinical effect of Jieyu Pills combined with Sertraline Hydrochloride in treating adolescent depression. Methods： A total of 80 first-onset adolescent depression patients admitted to Yulin Veterans Hospital from January 2023 to January 2024 were selected and divided into the control group and the trial group using the random number table method， with 40 cases in each group. The control group received oral Sertraline Hydrochloride Tablets，while the trial group received Jieyu Pills in addition to Sertraline Hydrochloride. Both groups were treated for four weeks. The clinical effects， relative power of neurotransmitters [5-hydroxytryptamine （5-HT）， norepinephrine （NE）， dopamine （DA）]， scores of Hamilton Depression Scale（HAMD）， and scores of Treatment Emergent Symptom Scale（TESS） were compared between the two groups before and after treatment. Results：The total effective rate was 95.00%（38/40） in the trial group and 77.50%（31/40） in the control group， the difference being significant between the two groups（P＜0.05）. After treatment， HAMD scores were decreased in both groups when compared with those before treatment（P＜0.05）， with the trial group showing lower HAMD scores than the control group （P＜0.05）. After treatment， the relative power of 5-HT， NE， and DA were increased significantly in both groups（ P＜0.05），with higher relative power observed in the trial group compared to the control group（ P＜0.05）. The incidence of adverse reactions during treatment was 2.50%（1/40） in the trial group and 17.50%（7/40） in the control group， the difference being significant （P＜0.05）. Conclusion： Jieyu Pills combined with Sertraline Hydrochloride improves clinical effect in treating adolescent depression， significantly alleviates depressive symptoms， enhances neurotransmitter relative power，and reduces adverse reactions.