Objective This systematic review aimed to provide a comprehensive overview of the application of machine learning (ML) in predicting multiple adverse drug events (ADEs) using electronic health record (EHR) data. Methods Systematic searches were conducted using PubMed, Web of Science, Embase, and IEEE Xplore from database inception until 21 November 2023. Studies that developed ML models for predicting multiple ADEs based on EHR data were included. Results Ten studies met the inclusion criteria. Twenty ML methods were reported, most commonly random forest (RF, n = 9), followed by AdaBoost (n = 4), eXtreme Gradient Boosting (n = 3), and support vector machine (n = 3). The mean area under the summary receiver operator characteristics curve (AUC) was 0.76 (95% confidence interval [CI] = 0.26–0.95). RF combined with resampling-based approaches achieved high AUCs (0.9448–0.9457). The common risk factors of ADEs included the length of hospital stay, number of prescribed drugs, and admission type. The pooled estimated AUC was 0.72 (95% CI = 0.68–0.75). Conclusions Future studies should adhere to more rigorous reporting standards and consider new ML methods to facilitate the application of ML models in clinical practice.