Background. Cemento-ossifying fibroma (COF) is a type of benign fibro-osseous tumor that mainly occurs in the maxillofacial region. Bone reconstruction after the surgery is often performed with bone transplantation. However, the present case report describes the accurate diagnosis and successful surgical resection of a COF with periosteum preservation, after which the defect was completely and spontaneously filled with the newly formed bone through a natural process. Case Presentation. A 32-year-old Iranian female patient presented with a history of gradual development of painful swelling, spontaneous pain, and lower lip and chin hypoesthesia in the lower third of the left side of her face. The dome-shaped swelling was tender. The patient was suffering from renal infection and urethral prolapse and was taking folic acid. She also mentioned a positive family history of similar swellings in her mother and uncle. Intraoral examination indicated a lesion in buccal and lingual vestibules extending from the first premolar to the third molar teeth. It had a firm consistency, and the covering mucosa was normal in terms of color and texture. The aspiration test was negative. The lesion had caused severe mobility of the second premolar and first and second molar teeth. Panoramic radiography revealed an extensive well-defined unilocular radiolucency. Significant knife-edge resorption of the first and second molar roots at the involved site and thinning of the alveolar crest and inferior border of the mandible were also clear. Cone-beam computed tomography showed severe expansion in the buccal and moderate expansion in the lingual aspect, causing thinning of both the buccal and lingual cortical plates. Histopathological analysis revealed neoplastic tissue mixed with fibrous connective tissue and several round and oval-shaped calcification foci. Immunohistochemical analysis confirmed the final diagnosis (COF) with the presence of SMA-8. The lesion was removed by enucleation and curettage, while the periosteum was carefully preserved. Fixation with screw and plate was also performed. Conclusions. Correct diagnosis of COF and precise implementation of the periosteal osteogenesis technique, in this case, resulted in entirely and spontaneously bone regeneration, which was a rare and favorable outcome with minimum cost and complications for the patient.