Bullous pemphigoid is an acquired autoimmune subepidermal blistering disease that can arise following exposure to systemic medication, referred to as drug-induced bullous pemphigoid. Drug-induced bullous pemphigoid is a rare but potentially serious immune-related adverse event that should be considered in patients with advanced malignancies undergoing immunotherapy, with immune checkpoint inhibitors emerging in particular as a well-documented drug association in drug-induced bullous pemphigoid. We present a 74-year-old female with recurrent metastatic programmed cell death-ligand 1-positive squamous cell carcinoma of the head and neck area who developed drug-induced bullous pemphigoid in the setting of immunotherapy with a novel immunoglobulin-like transcript 4 inhibitor (MK-4830) in combination with pembrolizumab. Treatment with upadacitinib, a Janus-associated kinase-1 inhibitor, was pursued for significantly disabling disease that was recalcitrant to standard therapies and ultimately transition to palliative care. Follow-up at 4 weeks demonstrated good response. This is the first report describing the use of a Janus-associated kinase inhibitor for the treatment of bullous pemphigoid.