Purpose: Previous studies have shown that persistent post-stroke depression (PSD) was associated with unfavorable prognosis. The aim of this multicenter prospective study was to investigate the predictors associated with persistent PSD, develop a nomogram and validate its clinical usefulness by decision curve analysis (DCA). Patients and Methods: A total of 875 acute ischemic stroke patients from four hospitals were consecutively recruited and completed 1-year follow-ups. Sociodemographic indicators, vascular risk factors, clinical information, serum biochemical indicators and cytokines were collected on admission. The functional outcome was assessed at 1 year after stroke. Persistent depression was defined as having a presentation of depression at each follow-up points and the depressive symptoms occurring persistently since the diagnosis of depression. Results: There were 513 patients who experienced PSD during the 1-year follow-up, the cumulative incidence of PSD within 1 year was 58.6%. Persistent PSD was recorded in 289 patients, of which 59 (20.4%) result in unfavorable outcomes. The risk factors of persistent PSD in 1 year after stroke were the Hamilton Depression Scale-17 items (HAMD-17) score at admission, serum direct bilirubin and free serum thyroxine (FT4) level and activated partial thromboplastin time (APTT). Nomogram conducted based on these factors has a C-index (+/- standard deviation) of 0.655 +/- 0.039, and the DCA demonstrated that the nomogram had a favorable clinical utility. Conclusion: We found that persistent depression after stroke in the first-year time course after stroke was associated with HAMD-17 score at admission, lower serum direct bilirubin and FT4 level, and APTT. A nomogram was developed with advisable clinical usefulness in our study.