BACKGROUND: Transdifferentiation of hairy cell leukemia to histiocytic sarcoma (HS) has not been previously reported in the head and neck. Given the rarity of HS, it can pose a challenge to diagnose this aggressive malignancy. CASE PRESENTATION: A 93-year-old male with a complex medical history presented with symptomatic and mobile lower anterior teeth. No intraoral growth mass was present initially and radiographic examination showed a radiolucent lesion in the anterior mandible. An incisional biopsy under local anesthesia was performed and histopathologic examination revealed a malignant sarcoma which upon further clinical, immunohistochemical, and molecular workup, confirmed the diagnosis. DIAGNOSIS: Initial histopathologic evaluation of the biopsy rendered a provisional diagnosis of undifferentiated pleomorphic sarcoma. The case was referred to a tertiary care center for complete medical workup and additional ancillary studies where it was definitively diagnosed as a HS. The patient passed away a month after this HS diagnosis.