The aim of this study was to predict the long-term survival probability of patients with ampullary adenocarcinoma (AAC), which would provide a theoretical basis for the long-term care of these patients.Data on patients with AAC during 2004-2015 were obtained from the Surveillance, Epidemiology, and End Results database, which were split at a 7:3 ratio into two independent cohorts: training and testing cohorts. Differences in survival between the two groups were tested using the Kaplan-Meier estimator and log-rank test methods. We constructed six survival analysis methods: the American Joint Committee on Cancer TNM stage, Cox Proportional Hazards regression, CoxTime, DeepSurv, XGBoost Survival Embeddings, and Random Survival Forest. The performances of these models were evaluated using the C-index, receiver operating characteristic (ROC), and calibration curves.This study included 2,935 patients with AAC. Univariate Cox regression analyses of the training cohort indicated that race, marital status at diagnosis, scope of regional lymph node surgery, tumor grade, summary stage, American Joint Committee on Cancer stage, TNM stage T, and TNM stage N were important factors affecting survival (P ​< ​0.05). The results of the C-index indicated that DeepSurv performed the best among the six models, with the highest C-index of 0.731. The areas under the ROC curves of the DeepSurv model at the 1-year, 3-year, 5-year, and 10-year time points were 0.823, 0.786, 0.803, and 0.813, respectively. The calibration curve indicated that DeepSurv performed well, with good calibration.Machine learning models such as DeepSurv have a stronger performance in the survival analysis of patients with AAC.© 2022 The Author(s).