Background Patients with COVID-19 in the intensive care unit (ICU) have a high mortality rate, and methods to assess patients’ prognosis early and administer precise treatment are of great significance. Objective The aim of this study was to use machine learning to construct a model for the analysis of risk factors and prediction of mortality among ICU patients with COVID-19. Methods In this study, 123 patients with COVID-19 in the ICU of Vulcan Hill Hospital were retrospectively selected from the database, and the data were randomly divided into a training data set (n=98) and test data set (n=25) with a 4:1 ratio. Significance tests, correlation analysis, and factor analysis were used to screen 100 potential risk factors individually. Conventional logistic regression methods and four machine learning algorithms were used to construct the risk prediction model for the prognosis of patients with COVID-19 in the ICU. The performance of these machine learning models was measured by the area under the receiver operating characteristic curve (AUC). Interpretation and evaluation of the risk prediction model were performed using calibration curves, SHapley Additive exPlanations (SHAP), Local Interpretable Model-Agnostic Explanations (LIME), etc, to ensure its stability and reliability. The outcome was based on the ICU deaths recorded from the database. Results Layer-by-layer screening of 100 potential risk factors finally revealed 8 important risk factors that were included in the risk prediction model: lymphocyte percentage, prothrombin time, lactate dehydrogenase, total bilirubin, eosinophil percentage, creatinine, neutrophil percentage, and albumin level. Finally, an eXtreme Gradient Boosting (XGBoost) model established with the 8 important risk factors showed the best recognition ability in the training set of 5-fold cross validation (AUC=0.86) and the verification queue (AUC=0.92). The calibration curve showed that the risk predicted by the model was in good agreement with the actual risk. In addition, using the SHAP and LIME algorithms, feature interpretation and sample prediction interpretation algorithms of the XGBoost black box model were implemented. Additionally, the model was translated into a web-based risk calculator that is freely available for public usage. Conclusions The 8-factor XGBoost model predicts risk of death in ICU patients with COVID-19 well; it initially demonstrates stability and can be used effectively to predict COVID-19 prognosis in ICU patients.