Abstract Background The World Health Organization has highlighted the risk of Disease X, urging pandemic preparedness. Coronavirus disease 2019 (COVID-19) could be the first Disease X; therefore, understanding the epidemiological experiences of COVID-19 is crucial while preparing for future similar diseases. Methods Prediction models for COVID-19 severity risk in hospitalized patients were constructed based on four machine learning algorithms, namely, logistic regression, Cox regression, support vector machine (SVM), and random forest. These models were evaluated for prediction accuracy, area under the curve (AUC), sensitivity, and specificity as well as were interpreted using SHapley Additive exPlanation. Results Data were collected from 1,485 hospitalized patients across 6 centers, comprising 1,184 patients with severe or critical COVID-19 and 301 patients with nonsevere COVID-19. Among the four models, the SVM model achieved the highest prediction accuracy of 98.45%, with an AUC of 0.994, a sensitivity of 0.989, and a specificity of 0.969. Moreover, oxygenation index (OI), confusion, respiratory rate, and age were found to be predictors of COVID-19 severity risk. Conclusions SVM could accurately predict COVID-19 severity risk; thus, it can be prioritized as a prediction model. OI is the most critical predictor of COVID-19 severity risk and can serve as the primary and independent evaluation indicator.