Avascular osteonecrosis of the jaw (ONJ) may occur as a consequence of several conditions, even including chemotherapy treatment in patients affected by tumors or osteoporosis. We report our clinical experience in treating bisphosphonate-induced ONJ with a therapeutic methodology that includes ozone therapy as a new and original approach for the clinical management of maxillary necrotic lesions. Of 58 patients with ONJ observed at our department, 33 gave their informed consent to be part of the research and were treated according to a therapeutic approach, which included noninvasive surgery associated with pre- and postsurgical cycles of ozone therapy consisting of eight sessions lasting 3 minutes each besides antibiotic and antifungal therapies. Outcomes showed how ozone therapy increases the benefits of surgical and pharmacologic treatments, increasing the complete healing of the lesions with the disappearance of symptoms and brings cases of lesion progression down to zero. In conclusion, ozone therapy is a reliable presidium in treatment of ONJ; its benefits are remarkable and improve significantly the outcomes of the surgical approach.