The mandible is one of the most affected bones in Langerhans cell histiocytosis (LCH), along with the skull, ribs, and vertebrae. Oral lesions may be the first/only sign of the condition, which increases the importance of early and assertive diagnosis. Our goal is to report a case of a 3-year-old male with LCH in the mandible, highlighting the challenging diagnosis. The patient had a persistent swelling in the right submandibular region and was referred to Erasto Gaertner Cancer Center with a main hypothesis of odontogenic infection/osteomyelitis. Histopathologic analysis of an oral biopsy specimen suggested a central giant cell lesion, but questions remained about the real nature of the lesion. Lymph node biopsy showed multifocal involvement by atypical and eosinophilic histiocyte aggregates and immunohistochemical analysis confirmed the diagnosis of LCH through positive tests for CD1a, CD68, S-100, and vimentin. The patient was treated by the pediatric oncology team with exclusive chemotherapy with a good outcome. The mandible is one of the most affected bones in Langerhans cell histiocytosis (LCH), along with the skull, ribs, and vertebrae. Oral lesions may be the first/only sign of the condition, which increases the importance of early and assertive diagnosis. Our goal is to report a case of a 3-year-old male with LCH in the mandible, highlighting the challenging diagnosis. The patient had a persistent swelling in the right submandibular region and was referred to Erasto Gaertner Cancer Center with a main hypothesis of odontogenic infection/osteomyelitis. Histopathologic analysis of an oral biopsy specimen suggested a central giant cell lesion, but questions remained about the real nature of the lesion. Lymph node biopsy showed multifocal involvement by atypical and eosinophilic histiocyte aggregates and immunohistochemical analysis confirmed the diagnosis of LCH through positive tests for CD1a, CD68, S-100, and vimentin. The patient was treated by the pediatric oncology team with exclusive chemotherapy with a good outcome.