Herpes simplex virus (HSV) infections are common in the European population, typically presenting with mucocutaneous and anogenital manifestations. However, disseminated infections and organ involvement are rare, usually occurring in immunocompromised individuals, particularly after hematopoietic stem cell or solid organ transplantation. HSV1/2-induced hepatitis is infrequent but can result in acute liver failure (ALF) and increased mortality. We present a case of fulminant ALF caused by disseminated primary HSV2 infection in a fifty-year-old male with rheumatoid arthritis treated with the JAK-inhibitor upadacitinib for 3 months prior to presentation. Clinical examination revealed severe oropharyngeal mucositis and hepatic encephalopathy. Initial laboratory results showed bicytopenia, significantly elevated transaminases, bilirubin, inflammatory markers, and severe coagulopathy. Empirical treatment with an antimicrobial regimen, intravenous aciclovir, acetylcysteine, and plasmapheresis (PPH) was initiated. The patient was listed for urgent liver transplantation based on King's College criteria. Further investigations revealed a high viral load of HSV2 DNA in the blood, and transjugular liver biopsy confirmed extensive liver necrosis with positive HSV staining. Despite antiviral therapy, the HSV2 viral load remained high, indicating resistance, and the patient was deemed "nontransplantable" due to clinical deterioration with progressive hepatic coma, hemorrhagic-septic shock, multiorgan failure, and secondary bowel ischemia, ultimately leading to the patient's death from refractory shock. This is only the second documented case of fulminant ALF due to HSV2 hepatitis in a patient undergoing JAK inhibition, and the first involving upadacitinib. It highlights the importance of considering primary herpesvirus infection as a potential cause of ALF, particularly in immunocompromised patients, and underscores the need for early antiviral intervention to improve outcomes.