Objective: To study the effect of clonazepam combined with duloxetine on sleep quality in patients with depression. Methods: A total of 90 patients with depression in our hospital from November 2021 to October 2024 were randomly divided into two groups (n = 45) by lottery. The control group was treated with clonazepam, while the observation group was treated with clonazepam combined with duloxetine. Results: Before treatment, there was no significant difference in weight loss, depression, physical dysfunction, cognitive impairment, loss of interest, fatigue, and sleep disorder scores between the two groups (P>0.05). After treatment, the weight loss, depression, physical dysfunction, cognitive impairment, loss of interest, fatigue, and sleep disorder scores in the observation group were significantly lower than those in the control group (P<0.05). The effective rate of the observation group was significantly higher than that of the control group (P<0.05). Before treatment, there was no significant difference in the scores of nighttime awakening, sleep maintenance, early awakening, daytime social function, daytime mood, snoring, deep breathing, and deep sleep ratio between the two groups (P>0.05). After treatment, the observation group had significantly lower scores of nighttime awakening, sleep maintenance, early awakening, daytime social function, daytime mood, snoring, deep breathing, and deep sleep ratio than the control group (P<0.05). Before treatment, there was no significant difference in the levels of norepinephrine, dopamine, and serotonin between the two groups(P>0.05). After treatment, the levels of neurotransmitters in the observation group were higher than those in the control group (P<0.05). Conclusion: Clonazepam combined with duloxetine has a significant therapeutic effect on depression, can effectively regulate the levels of neurotransmitters, and significantly improve the sleep quality of patients.0.