Crigler-Najjar (CN) syndrome is a rare genetic disease characterized by hyperbilirubinemia due to a deficiency in the hepatic enzyme UDP-glucuronosyl-transferase. We describe the first case of total knee arthroplasty in a patient with CN syndrome (type II). This procedure was complicated by kernicterus 1 week after hospital discharge. He also developed Klebsiella bacteremia and sepsis, requiring a brief ICU stay. He was discharged in good condition 2 months later. It is evident that physicians involved in the care of patients with CN syndrome in the peri-operative period need to have a high index of suspicion for the development of severe hyperbilirubinemia and kernicterus in order to appropriately manage and, possibly, prevent this complication. A literature review and intra-operative observations provide insight into the possible relationship between hyperbilirubinemia and osteoarthritis as well as the peri-operative considerations to be made for this group of patients.