ObjectivePost-stroke depression (PSD) is one of the most common and severe neuropsychological sequelae after stroke. Using a prediction model composed of multiple predictors may be more beneficial than verifying the predictive performance of any single predictor. The primary objective of this study was to construct practical prediction tools for PSD at discharge utilizing a decision tree (DT) algorithm. MethodsA multi-center prospective cohort study was conducted from May 2018 to October 2019 and stroke patients within seven days of onset were consecutively recruited. The independent predictors of PSD at discharge were identified through multivariate logistic regression with backward elimination. Classification and regression tree (CART) algorithm was employed as the DT model's splitting method. ResultsA total of 876 stroke patients who were discharged from the neurology departments of three large general Class A tertiary hospitals in Wuhan were eligible for analysis. Firstly, we divided these 876 patients into PSD and non-PSD groups, history of coronary heart disease (OR = 1.835; 95 % CI, 1.106–3.046; P = 0.019), length of hospital stay (OR = 1.040; 95 % CI, 1.013–1.069; P = 0.001), NIHSS score (OR = 1.124; 95 % CI, 1.052–1.201; P = 0.001), and Mini mental state examination (MMSE) score (OR = 0.935; 95 % CI, 0.893–0.978; P = 0.004) were significant predictors. The subgroup analysis results have shown that hemorrhagic stroke, history of hypertension and higher modified Rankin Scale score (mRS) score were associated with PSD at discharge in the young adult stroke patients. ConclusionsSeveral predictors of PSD at discharge were identified and convenient DT models were constructed to facilitate clinical decision-making.