Background: Chronic total occlusion (CTO) remains the most challenging procedure in coronary artery disease (CAD) for interventional cardiology. Although some clinical risk factors for CAD have been identified, there is no personalized prognosis test available to confidently identify patients at high or low risk for CTO CAD. This investigation aimed to use a machine learning algorithm for clinical features from clinical routine to develop a precision medicine tool to predict CTO before CAG. Methods: Data from 1473 CAD patients were obtained, including 1105 in the training cohort and 368 in the testing cohort. The baseline clinical characteristics were collected. Univariate and multivariate logistic regression analyses were conducted to identify independent risk factors that impact the diagnosis of CTO. A CTO predicting model was established and validated based on the independent predictors using a machine learning algorithm. The area under the curve (AUC) was used to evaluate the model. Results: The CTO prediction model was developed with the training cohort using the machine learning algorithm. Eight variables were confirmed as ‘important’: gender (male), neutrophil percentage (NE%), hematocrit (HCT), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), ejection fraction (EF), troponin I (TnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The model achieved good concordance indices of 0.724 and 0.719 in the training and testing cohorts, respectively. Conclusions: An easy-to-use tool to predict CTO in patients with CAD was developed and validated. More research with larger cohorts are warranted to improve the prediction model, which can support clinician decisions on the early discerning CTO in CAD patients.