Ameloblastic fibro-odontosarcoma (AFOS) is an extremely rare malignant mixed odontogenic tumor. The ectomesenchymal part of the neoplasm shows malignancy, whereas the epithelial component is rather benign. In addition, small areas with deposition of enamel matrix and dentine material are seen. The rarity of this neoplasm and microscopic similarities with other malignant and benign tumors can lead to diagnostic problems. Here, we describe the histopathologic features of a new case of AFOS of the mandible in a 34-year-old female patient. It is essential for oral pathologists to be familiar with the microscopic features of this rare neoplasm to have a proper diagnosis. This is also the first reported case of AFOS that closely resembles osteosarcoma in some areas.