Objective: To observe the efficacy and safety of acupoint application combined with anti-depressants on insomnia in depression patients and its role in improving insomnia syndrome. Methods: A total of 162 depression patients were divided into a research group (n=86) and in the control group (n=76) randomly. The research group was treated with acupoint application combined with anti-depressants and the control group was treated with anti-depressants alone. The trial lasted 6 weeks. Hamilton Depression scales (HAMD) and Hamilton Anxiety scales (HAMA) were applied to evaluate the depression and anxiety status on the baseline and 1st, 2ed, 6th after the treatment respectively. The insomnia severity and efficacy were evaluated with Pittsburgh Sleep Quality Index (PSQI) at the same time and the safety was evaluated by Treatment Emergent Symptom Scale (TESS) and laboratory examination. Results: The HAMD scores of both groups were 8.62±2.90 and 10.14±3.38, the scores in the research group was lower than that in the control group (t=3.0805, P=0.0024). The HAMA scores of both groups were 6.93±2.19 and 10.30±3.55 which declined significantly when compared with before treatment, the scores of the research group was lower than that in the control group (t=7.3614, P<0.001). The PSQI scores of both groups were 5.23±1.90 and 8.14±3.11, which declined significantly when compared with before treatment, the scores in the research group was lower than that in the control group (t=7.2771, P<0.001). The incidence of pruritus in the research group is higher than that in the control group but the incidence of insomnia is much lower. Conclusion: Acupoint application combined with anti-depressants demonstrated to be effective and safe in the treatment of depression, and more superior in improving insomnia syndrome than anti-depressants alone.