Abstract Human herpesvirus 6 (HHV-6) is a significant pathogen following solid organ transplantation. Here, we report on a 64-year-old female with cirrhosis related to non-alcoholic fatty liver disease who underwent orthotopic allogeneic liver transplantation and was ultimately diagnosed with HHV-6 encephalitis through cerebrospinal fluid analysis and MRI. Empirical treatment with daily ganciclovir was initiated according to characteristics indicative of viral encephalitis 3 days before confirmed diagnosis. Subsequent improvement in symptoms was observed, with clearance of HHV-6 from the blood. The complex diagnosis and management of this case accentuates the possibility of serious consequences of HHV-6 infection in postoperative liver transplant patients. Clinicians must maintain a high index of suspicion for HHV-6 reactivation, especially given its association with immunosuppressive drug regimens. Prompt recognition and initiation of antiviral therapy are paramount, particularly when patients present with fever or psychiatric symptoms, as these may indicate HHV-6 encephalitis.