Objective: To observe the clinical effect and safety of traditional Chinese medicine compound combined with Western medicine in the treatment of post-stroke depression.Methods: This study adopted a prospective design and included a total of 126 patients with post-stroke depression (from February 2023 to February 2025), who were divided into a control group (63 cases, paroxetine Hydrochloride tablets) and an observation group (63 cases, Shunao Jieyu Decoction + Paroxetine Hydrochloride Tablets). Comparisons were made between groups based on the same clinical data.Results: The observation group had a high effective rate of treatment, and the emotional score, TCM syndrome score, and neurological dysfunction score decreased, with P < 0.05. There was no significant difference in the occurrence of adverse reactions between the groups (P > 0.05). Conclusion: The combination of Shunao Jieyu Decoction and Paroxetine Hydrochloride Tablets can significantly improve the clinical efficacy of patients, alleviate depressive symptoms and promote the recovery of neurological function, and has good safety.