Juvenile xanthogranuloma (JXG) is a clonal non-Langerhans cell histiocytic disorder characterized by a variety of cutaneous and non-cutaneous manifestations, predominantly in children. The mitogen-activated protein kinase pathway (MAPK) is a key driver in many histiocytic disorders, including JXG. We report a rare presentation of JXG in the mastoid bone of a which recurred after surgery and was refractory to two lines of chemotherapy before responding to the MEK inhibitor trametinib, even in the absence of an identifiable MAPK pathway mutation. MEK inhibitors may be a therapeutic option for this sometimes difficult to treat disease.