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Background Risk scores can be useful in clinical risk stratification and accurate allocations of medical resources, helping health providers improve patient care. Point-based scores are more understandable and explainable than other complex models and are now widely used in clinical decision making. However, the development of the risk scoring model is nontrivial and has not yet been systematically presented, with few studies investigating methods of clinical score generation using electronic health records. Objective This study aims to propose AutoScore, a machine learning–based automatic clinical score generator consisting of 6 modules for developing interpretable point-based scores. Future users can employ the AutoScore framework to create clinical scores effortlessly in various clinical applications. Methods We proposed the AutoScore framework comprising 6 modules that included variable ranking, variable transformation, score derivation, model selection, score fine-tuning, and model evaluation. To demonstrate the performance of AutoScore, we used data from the Beth Israel Deaconess Medical Center to build a scoring model for mortality prediction and then compared the data with other baseline models using the receiver operating characteristic analysis. A software package in R 3.5.3 (R Foundation) was also developed to demonstrate the implementation of AutoScore. Results Implemented on the data set with 44,918 individual admission episodes of intensive care, the AutoScore-created scoring models performed comparably well as other standard methods (ie, logistic regression, stepwise regression, least absolute shrinkage and selection operator, and random forest) in terms of predictive accuracy and model calibration but required fewer predictors and presented high interpretability and accessibility. The nine-variable, AutoScore-created, point-based scoring model achieved an area under the curve (AUC) of 0.780 (95% CI 0.764-0.798), whereas the model of logistic regression with 24 variables had an AUC of 0.778 (95% CI 0.760-0.795). Moreover, the AutoScore framework also drives the clinical research continuum and automation with its integration of all necessary modules. Conclusions We developed an easy-to-use, machine learning–based automatic clinical score generator, AutoScore; systematically presented its structure; and demonstrated its superiority (predictive performance and interpretability) over other conventional methods using a benchmark database. AutoScore will emerge as a potential scoring tool in various medical applications.