Objective: This study aimed to systematically evaluate the effect of idebenone tablets in the treatment of post-stroke depression (Post-Stroke Depression, PSD). Methods: This study was a single-arm, prospective, observational study that recruited PSD patients who met the inclusion criteria after being assessed by the investigator between January 2022 and June 2023. The demographic characteristics, disease status, treatment status, and medication status of the patients were collected through questionnaires, and the Hamilton depression score of the patients was collected through the Case Report Form (CRF)to evaluate the effectiveness and safety of idebenone tablet treatment. Results: A total of 4902 PSD patients were included in this study, of which 2496 were males, accounting for 50.9%, and 2406 were females, accounting for 49.1%. According to the Hamilton Depression Rating Scale (HAMD), 13.9% were no depression at the first visit, 53.0% were mildly depressed, 24.3% were moderately depressed, and 8.8% were severely depressed. After treatment, the proportion of no depression was 26.1%, mild depression accounted for 53.3%, moderate depression accounted for 16.8%, and severe depression accounted for 3.8%, and the difference in the proportion of depression before and after treatment was statistically significant (P<0.05). Conclusion: Idebenone tablets can significantly reduce Hamilton’s depression score, suggesting that it has a significant therapeutic effect in improving PSD symptoms.