Background: Ampullary cancer is a rare biliary tract cancer arising from one of the three epithelial tissues in the region. Leveraging a large patient-level genomic database, this study aims to identify, explore, and describe the genetic landscape of ampullary carcinoma and its implications. Methods: A retrospective analysis of ampullary cancer samples was conducted using the AACR Project GENIE database. Analysis of recurrent somatic mutations at large and between patient populations, and co-occurrence and mutual exclusivity of mutations was conducted, with a p-value < 0.05. Results: The most frequent mutations were identified as TP53 (53.2%), KRAS (46.6%), and SMAD4 (16.6%). Mutational differences were noted between sexes, White vs. Non-white groups, and histopathological subtypes. Significant mutual exclusivity was found between KRAS and ERBB2. Co-occurrence was observed in the ARID1A mutation with KMT2D, ERBB2, and PIK3CA; CDKN2A with the SMAD4 and KRAS mutations; TP53 mutation with the CTNNB1 mutation; and KRAS co-occurred with an APC mutation. Reduced survival rates were seen in populations with the TP53 or KRAS mutation. Conclusions: This study provides a detailed descriptive genomic landscape of ampullary carcinoma, highlighting frequent mutations between patient groups and the mutational burden of the DNA damage response pathway in ampullary cancer, laying important groundwork for the development of therapeutic targets and more individualized treatment regimens.