Background Although deep learning has brought revolutionary changes in health care, reliance on manually selected cross-sectional images and segmentation remain methodological barriers. Purpose To develop and validate an automated preoperative artificial intelligence (AI) algorithm for tumor and lymph node (LN) segmentation with CT imaging for prediction of LN metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). Materials and Methods In this retrospective study, patients with surgically resected, pathologically confirmed PDAC underwent multidetector CT from January 2015 to April 2020. Three models were developed, including an AI model, a clinical model, and a radiomics model. CT-determined LN metastasis was diagnosed by radiologists. Multivariable logistic regression analysis was conducted to develop the clinical and radiomics models. The performance of the models was determined on the basis of their discrimination and clinical utility. Kaplan-Meier curves, the log-rank test, or Cox regression were used for survival analysis. Results Overall, 734 patients (mean age, 62 years ± 9 [SD]; 453 men) were evaluated. All patients were split into training (n = 545) and validation (n = 189) sets. Patients who had LN metastasis (LN-positive group) accounted for 340 of 734 (46%) patients. In the training set, the AI model showed the highest performance (area under the receiver operating characteristic curve [AUC], 0.91) in the prediction of LN metastasis, whereas the radiologists and the clinical and radiomics models had AUCs of 0.58, 0.76, and 0.71, respectively. In the validation set, the AI model showed the highest performance (AUC, 0.92) in the prediction of LN metastasis, whereas the radiologists and the clinical and radiomics models had AUCs of 0.65, 0.77, and 0.68, respectively (P < .001). AI model-predicted positive LN metastasis was associated with worse survival (hazard ratio, 1.46; 95% CI: 1.13, 1.89; P = .004). Conclusion An artificial intelligence model outperformed radiologists and clinical and radiomics models for prediction of lymph node metastasis at CT in patients with pancreatic ductal adenocarcinoma. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chu and Fishman in this issue.