Ameloblastic fibro-odontosarcoma (AFOS) is an extremely rare subtype of odontogenic sarcoma, with no more than 19 cases reported in the English literature to date. AFOS is a biphasic neoplasm, with deposits of dentin and enamel matrix. We herein present a case of AFOS with active epithelial proliferation in a 31-year-old female patient. The patient was referred to the West China Hospital of Stomatology (Chengdu, China) due to a 6-month history of a swelling in the left mandible. Following clinical and radiological examination, the initial preoperative diagnosis was ameloblastoma, with local invasion and the possibility of malignant transformation. Left hemimandibular resection was subsequently performed. The postoperative histopathological diagnosis was AFOS, accompanied by active epithelial proliferation. Immunohistochemically, cytokeratin (CK)14 and CK19 were intensely positive in the epithelium, whereas the mesenchymal cells were strongly positive for vimentin. The Ki-67 labeling index was considerably higher in the mesenchymal component (mean, 40%) compared with that in the epithelial element (mean, 5–8%). Three months after the surgical procedure, the patient remained clinically and radiologically disease-free.