BACKGROUND: Cancer patients receiving targeted therapies need to prevent QTc prolongation and life-threatening cardiovascular (CV) events to maintain a balanced benefit-risk ratio. This study aimed to develop an optimal prediction model for QTc prolongation risk and estimate its risk probability in cancer patients treated with oral tyrosine kinase inhibitors (TKIs). METHODS: This retrospective cohort study analyzed electronic medical records (EMR) of cancer patients newly treated with commonly used oral TKIs at a medical center between January 2016 and December 2020. QTc prolongation was defined as ≥ 450 ms in males and ≥ 470 ms in females using Bazett's formula. The study followed four key steps: (1) Managing missing data, (2) Identifying important variables, (3) Training and testing the best prediction models, (4). Estimating risk probability and determining cut-off points. Both univariate logistic regression (LR) and supervised machine learning (ML) approaches were used for variable selection. The backward LR method and seven ML algorithms were applied to train and test the prediction models. The best model was identified based on model performance, fitting criteria, area under the receiver operating characteristic curve (AUROC), risk probability cut-off points, and clinical relevance. RESULTS: The statistical 12-parameter model demonstrated excellent performance (AUROC = 0.89, sensitivity = 0.91, specificity = 0.75) and strong discrimination ability for risk probability prediction (AUROC = 0.78, cut-off = 0.46), outperforming other ML models. In the final best model: the baseline risk probability of QTc prolongation was 0.13, even in the absence of other contributing factors. Baseline QTc prolongation and a history of cardiovascular disease (excluding arrhythmia, cardiomyopathy, etc.) contributed the most to incremental risk probability (0.471 and 0.282, respectively), after controlling for other factors. The remaining 10 factors each contributed to an increased probability of QTc prolongation for more than 0.14 probability. CONCLUSIONS: A logistic regression model utilizing 12 easily accessible variables from EMRs outperformed ML models in predicting the risk probability of QTc prolongation in cancer patients newly treated with five oral TKIs. These findings serve as a valuable clinical reference for integrating digital monitoring into cardiovascular care for cancer survivors undergoing targeted therapy with TKIs. They also underscore the importance of screening baseline ECG before initiating TKIs to assess the risk of QTc prolongation, facilitating early intervention and prevention in the future.