Disseminated histoplasmosis (DH) is typically seen in patients with organ transplantation or human immunodeficiency virus and rarely presents with acute liver failure. Tumor necrosis factor inhibitors may be immunosuppressive but unlikely to result in DH. A 70-year-old woman with a history of psoriatic arthritis on infliximab presented with altered mental status, fevers, and severe liver injury. She was found to have DH, which resolved on antifungal agents. Because the use of tumor necrosis factor inhibitors has increased, providers should consider this uncommon infection in patients who present with cryptogenic severe liver injury.