Objectives: Heart failure (HF) is a common disease with a high hospital readmission rate. This study considered class imbalance and missing data, which are two common issues in medical data. The current study’s main goal was to compare the performance of six machine learning (ML) methods for predicting hospital readmission in HF patients. Methods: In this retrospective cohort study, information of 1,856 HF patients was analyzed. These patients were hospitalized in Farshchian Heart Center in Hamadan Province in Western Iran, from October 2015 to July 2019. The support vector machine (SVM), least-square SVM (LS-SVM), bagging, random forest (RF), AdaBoost, and naïve Bayes (NB) methods were used to predict hospital readmission. These methods’ performance was evaluated using sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Two imputation methods were also used to deal with missing data. Results: Of the 1,856 HF patients, 29.9% had at least one hospital readmission. Among the ML methods, LS-SVM performed the worst, with accuracy in the range of 0.57–0.60, while RF performed the best, with the highest accuracy (range, 0.90–0.91). Other ML methods showed relatively good performance, with accuracy exceeding 0.84 in the test datasets. Furthermore, the performance of the SVM and LS-SVM methods in terms of accuracy was higher with the multiple imputation method than with the median imputation method. Conclusions This study showed that RF performed better, in terms of accuracy, than other methods for predicting hospital readmission in HF patients.