TP53 is frequently mutated in various cancers, including pancreatic, hepatocellular, and biliary cancers. These mutations are often associated with poor patient survival and resistance to therapy. In this review, we focus on the progress made in elucidating the effects of TP53 on these cancers. Mutations in these three cancer types were chosen to review as they are related in their origins and to components of the hepatobiliary and pancreatic systems.