This work aimed to explore the utility of computed tomography (CT) radiomics with machine learning for distinguishing the pancreatic lesions prone to nondiagnostic ultrasound-guided fine-needle aspiration (EUS-FNA).498 patients with pancreatic EUS-FNA were retrospectively reviewed (Development cohort: 147 PDAC; Validation cohort: 37 PDAC). Pancreatic lesions not PDAC were also tested exploratively. Radiomics extracted from contrast-enhanced CT was integrated with deep neural networks (DNN) after dimension reduction. The receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were performed for model evaluation. And the explainability of the DNN model was analyzed by integrated gradients.The DNN model was effective in distinguishing PDAC lesions prone to nondiagnostic EUS-FNA (Development cohort: AUC = 0.821, 95% CI: 0.742-0.900; Validation cohort: AUC = 0.745, 95% CI: 0.534-0.956). In all cohorts, the DNN model showed better utility than the logistic model based on traditional lesion characteristics with NRI >0 (p < 0.05). And the DNN model had net benefits of 21.6% at the risk threshold of 0.60 in the validation cohort. As for the model explainability, gray-level co-occurrence matrix (GLCM) features contributed the most averagely and the first-order features were the most important in the sum attribution.The CT radiomics-based DNN model can be a useful auxiliary tool for distinguishing the pancreatic lesions prone to nondiagnostic EUS-FNA and provide alerts for endoscopists preoperatively to reduce unnecessary EUS-FNA.This is the first investigation into the utility of CT radiomics-based machine learning in avoiding nondiagnostic EUS-FNA for patients with pancreatic masses and providing potential preoperative assistance for endoscopists.