Objective: This study aimed to explore the efficacy of butylphthalide combined with sertraline in the treatment of post-stroke depression after ischemic stroke. Methods: A retrospective analysis was conducted on the clinical data of 90 patients with post-stroke depression admitted to a tertiary hospital in a certain city in China from March 2021 to March 2023. The patients were divided into an observation group and a control group, each consisting of 45 cases, based on different medication methods. The control group received sertraline treatment only, while the observation group was treated with butylphthalide combined with sertraline. Both groups completed an 8-week treatment course. The data after treatment were compared to systematically evaluate and compare the differences between the two groups in terms of clinical efficacy, levels of inflammatory factors, improvement in mood, and the incidence of adverse reactions. Results: The observation group performed significantly better than the control group in terms of inflammatory indicators, treatment effects, and mood states, with a lower incidence of adverse reactions and a higher overall effective rate. The differences between the groups were statistically significant (P < 0.05). During the treatment period, the incidence of adverse reactions in the observation group was 6.67%, and the overall effective rate was 84.44%; while in the control group, the incidence of adverse reactions was 11.1%, and the overall effective rate was 68.88%. The observation group not only had a lower risk of adverse reactions but also showed more significant therapeutic effects, indicating a significant difference in the efficacy of drug intervention between the two groups, which was statistically significant (P < 0.05). Conclusion: The combination of butylphthalide and sertraline is effective in treating post-stroke depression after ischemic stroke, improving multiple indicators of patients, enhancing their quality of life, and has high safety, presenting a promising clinical application prospect.