Liver transplant is a rare phenomenon for pyruvate kinase deficiency (PKD)-related liver disease and can be mediated by multiple mechanisms. In this report, we present a 55-year-old man with PKD who had acute-on-chronic liver failure with kidney failure and marked hyperbilirubinemia. His liver disease was from recurrent cholangitis, cholestasis from hemolysis, and iron deposition (likely from both repeated transfusions in youth and chronic hemolysis), all consequences of his PKD. He received a liver transplant and had a good outcome. Our case highlights the mechanisms of liver injury in PKD and successful transplantation for this rare complication.