Objective: To study the therapeutic effect of modified Chaihu Shugan San combined with paroxetine on patients with depression. Method: Sixty eight patients with depression admitted to our hospital from January 2023 to January 2025 were randomly divided into two groups using a random number table. The observation group was treated with modified Chaihu Shugan San (once daily) combined with paroxetine for 4 weeks, while the control group was treated with paroxetine alone (once daily, for 4 weeks). The clinical efficacy, psychological status, and medication safety of the patients were evaluated. Result: The psychological state scores of the observation group patients were lower than those of the control group, (P<0.05)； The total effective rate of the observation group patients was 100.00%, which was higher than the control group"s 88.24%, (P<0.05)； There was no difference in the incidence of adverse reactions between the two groups, (P>0.05)； The traditional Chinese medicine syndrome scores of the observation group were lower than those of the control group, (P<0.05). Conclusion: Chaihu Shugan San combined with paroxetine has good clinical efficacy in treating depression, significantly improving patients" depressive symptoms, and has high safety.