Abstract： Objective： To observe the clinical efficacy of Five-Element Music combined with high-frequency repetitive transcranial magnetic stimulation （HF-rTMS） in treating depression and its effects on serum forkhead box protein O1 （FOXO1） and 5-hydroxytryptamine （5-HT） levels. Methods：A total of 130 depression patients admitted to Shaoxing Seventh People's Hospital from December 2023 to January 2025 were selected and randomly divided into a control group and a study group using the random number table method，with 65 cases in each group. The control group received conventional treatment， while the study group received Five-Element Music combined with HF-rTMS. Clinical efficacy， incidence of adverse reactions， Pittsburgh Sleep Quality Index （PSQI）， Hamilton Depression Rating Scale （HAMD） scores， Beck Depression Inventory-Ⅱ（BDI-Ⅱ） scores， and serum levels of FOXO1 and neurotransmitters [5-HT，dopamine （DA），norepinephrine （NE）] were compared between the two groups. Results： After treatment， the total effective rate was 93.85% （61/65） in the study group， significantly higher than that of 78.46%（ 51/65） in the control group（ P＜0.05）. PSQI scores decreased in both groups after treatment（ P＜0.05），with lower scores in the study group （P＜0.05）. HAMD and BDI-Ⅱscores decreased in both groups （P＜0.05），with lower scores in the study group （P＜0.05）. FOXO1 levels decreased in both groups （P＜0.05），while 5-HT，DA，and NE levels increased （P＜0.05）. The study group had lower FOXO1 levels and higher 5-HT，DA，and NE levels than the control group（ P＜0.05）. The incidence of adverse reactions was 18.46%（ 12/65） in the study group and 12.31%（ 8/65） in the control group， with no significant difference between the two groups （P＞0.05）. Conclusion： Five-Element Music combined with HF-rTMS demonstrates significant efficacy in treating depression， improving sleep quality and psychological status， regulating serum FOXO1 and neurotransmitter levels， without significantly increasing adverse reactions.