Abstract：Objective：To observe the clinical effect of modified Chaihu Shugan Powder combined with Butylphthalide Capsules for post-stroke depression (PSD) and its effect on levels of neurobiochemical markers (S100B protein) in serum. Methods： A total of 62 PSD patients in Yongjia Hospital of Traditional Chinese Medicine form January 1， 2021 to November 30， 2023 were selected as the research subjects and randomly divided into two groups of 31 each according to the random number table method. The control group was treated with Butylphthalide Capsules， and the observation group was treated with Chaihu Shugan Powder in addition to the control group's treatment plan. Both groups were treated for three courses， with 20 days being one course of treatment. Compared the clinical effects in the two groups. Measured and compared the changes in serum S100B protein levels before treatment， and after one course of treatment， and two and three courses of treatment. Compared the scores of Hamilton Depression Scale (HAMD) and National Institutes of Health Stroke Scale (NIHSS) before and after treatment between the two groups. Compared the Treatment-Emergent Symptom Scale (TESS) scores between the two groups. Results：After one course of treatment，and two and three courses of treatment，the serum S100B protein levels in both groups were decreased when compared with those before treatment，and the serum S100B levels in the observation group were lower than those in the control group at all stages， differences being significant (P＜0.05). After three courses of treatment， the HAMD and NIHSS scores in both groups were decreased when compared with those before treatment， and the HAMD and NIHSS scores in the observation group were lower than those in the control group， differences being significant (P＜0.05). The total effective rate was 90.32% in the observation group， which was higher than that of 61.29% in the control group，the difference being significant (P＜0.05). After one course of treatment，and two and three courses of treatment， the TESS scores in the observation group in each stage were lower than those in the control group， differences being significant (P＜0.05). Conclusion： Modified Chaihu Shugan Powder combined with Butylphthalide Capsules can treat post-stroke depression by reducing serum S100B protein levels and improving depressive symptoms. It has good clinical efficacy and certain safety.