Abstract: Objective To investigate the clinical effect of Xiashi Shuimian Yihao on depressive sleep disorder with deficiency syndrome and its effect on serotonin (5-HT) and norepinephrine (NE). Methods A total of 120 patients with depressive sleep disorder diagnosed as deficient syndrome of TCM in our hospital from December 2016 to December 2017 were divided into two groups by random number method, with 60 cases in each group. The control group was treated with fluoxetine hydrochloride capsules, and the observation group was treated with Xiashi Shuimian Yihao based on the control group. After treatment, Hamilton Depression Scale (HAMD) score, Ascension Insomnia Scale (AIS) score, serum5-HT, serum NE level, adverse reactions (dizziness headache, nausea, loss of appetite, dry mouth), and effect of two groups were compared. Results Total effective rate of observation group (88.33%) was significantly higher than that of the control group (68.33%, P < 0.05). After treatment, the HAMD and AIS scores of the two groups were significantly lower (all P < 0.05), the HAMD and AIS scores of observation group was lower than control group (all P < 0.05). After treatment, serum 5-HT and NE levels were significantly increased in the two groups (all P < 0.05), and serum 5-HT and NE levels of observation group was significantly higher than the control group (all P < 0.05). The adverse incidence of observation group (18.33%) was significantly lower than control group (41.67%, P < 0.05). Conclusion Xiashi Shuimian Yihao could effectively treat depressive sleep disorder with deficiency syndrome, alleviate the symptoms of insomnia and reduce the adverse reactions. The mechanism may be related to its upregulation of serum serotonin and norepinephrine.