Objectives Development and validation of a computed tomography urography (CTU)-based machine learning (ML) model for prediction of preoperative pathology grade of upper urinary tract urothelial carcinoma (UTUC).Methods A total of 140 patients with UTUC who underwent CTU examination from January 2017 to August 2023 were retrospectively enrolled. Tumor lesions on the unenhanced, medullary, and excretory periods of CTU were used to extract Features, respectively. Feature selection was screened by the Pearson and Spearman correlation analysis, least absolute shrinkage and selection operator algorithm, random forest (RF), support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost). The logistic regression (LR) was used to screen for independent influencing factors of clinical baseline characteristics. Machine learning models based on different feature datasets were constructed and validated using algorithms such as LR, RF, SVM, and XGBoost. By computing the selected features, a radiomics score was generated, and a diverse feature dataset was constructed. Based on the training set, 16 ML models were created, and their performance was evaluated using the validation set for metrics including sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC), and others.Results The training set consisted of 98 patients (mean age: 64.5 +/- 10.5 years; 30 males), whereas the validation set consisted of 42 patients (mean age: 65.3 +/- 9.78 years; 17 males). Hydronephrosis was the best independent influence factor (p < 0.05). The RF model had the best performance in predicting high-grade UTUC, with AUC of 0.914 (95% Confidence Interval [95%CI] 0.852-0.977) and 0.903 (95%CI 0.809-0.997) in the training set and validation set, and accuracy of 0.878 and 0.857, respectively.Conclusions An ML model based on the RF algorithm exhibits excellent predictive performance, offering a non-invasive approach for predicting preoperative high-grade UTUC.