BackgroundIschemic stroke is a common and serious disease with economic and healthcare burdens. Predicting the unfavorable discharge outcome of patients is essential for formulating appropriate treatment strategies and providing personalized care. Therefore, this study aims to establish and validate a prediction model based on machine learning methods to accurately predict the discharge outcome of ischemic stroke patients, providing valuable information for clinical decision making. MethodsThe derivation data consisted of 964 patients from Guangdong Provincial People's Hospital and was used for training and internal validation. A favourable discharge outcome was defined as a National Institutes of Health Stroke Scale score of ≤1 or a decrease of ≥8 points compared to the admission score. A predictive model was created based on 88 medical characteristics gathered during the patient's initial admission, using nine machine learning algorithms. The model's predictive performance was compared using various evaluation metrics. The final model's feature importance was ranked and explained using the Shapley additive explanation method. FindingsThe random forest model demonstrated the greatest discriminative ability among the nine machine learning models. We created an interpretable random forest model by ranking and reducing the features based on their importance, which included eight features. In internal validations, the final model accurately predicted the discharge outcomes of ischemic stroke with AUC values of 0.903 and has been translated into a convenient tool to facilitate its utility in clinical settings. ConclusionsOur explainable ML model was not only successfully developed to accurately predict discharge outcomes in patients with ischemic stroke and it mitigated the concern of the “black-box” issue with an undirect interpretation of the ML technique.