To investigate the effects of acupuncture combined with Supplemented Peripatetic Decoction on homocysteine (Hcy), 5-hydroxytryptaminergic(5-HT), cell factor and therapeutic effect on patients with depression. Methods: Total 97 patients with depression were selected in our hospital from May 2015 to October 2015 were randomly divided into observation group (49 cases) and control group (48 cases). The control group was treated with Pa Rossi Dean therapy, and the observation group was treated with acupuncture combined with Supplemented Peripatetic Decoction. The treatment lasted for 2 months. The therapeutic effect, Hamilton Depression table (HAMD) each factor score, Hcy, 5-HT, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and adverse drug reaction were compared between the two groups before and after treatment. Results: The total effective rate of the observation group (93.88%) was significantly higher than that of the control group (70.83%) (P<005); Cognitive impairment, sleep disorder, mental anxiety and somatic anxiety dropped significantly in two groups after treatment (P<005); The scores of cognitive impairment, sleep disorder, mental anxiety and somatic anxiety in the observation group were significantly lower than those in the control group (P<005); The serum level of Hcy dropped significantly after treatment in two groups, and the 5-HT level increased significantly (P<005); After treatment, the serum Hcy level of the observation group became significantly lower than that of the control group, 5-HT was significantly higher than that of the control group (P<005); After treatment, the plasma levels of TNF-α and IL-6 decreased significantly in the two groups (P<005); After treatment, the levels of plasma TNF-α and IL-6 in the observation group were significantly lower than those in the control group (P<005); The incidence of adverse reactions in the observation group was lower than the control group (P<005). Conclusion: Acupuncture combined with Supplemented Peripatetic Decoction has significant curative effect in the treatment of depression patients. It can reduce the level of Hcy, increase 5-HT, reduce TNF-α, IL-6 level, with safe and reliable results, which is worth studying.