BACKGROUNDS: The prognosis of patients with osteosarcoma in many cases remains poor, and life expectancy with lung metastases is around 12 months. Chemotherapy and radiotherapy can only temporarily control neoplastic progression, followed by developing chemo and radioresistant tumours. METHODS: This is a retrospective observational study on 15 patients diagnosed with osteosarcoma and treated by a multitherapy approach. The multitherapy consisted of somatostatin and analogous (octreotide) all-trans-retinoic acid (ATRA), β-Carotene, axerophthol dissolved in vitamin E, vitamin D, vitamin C, melatonin (MLT), proteoglycans, glycosaminoglycans, hydroxyurea, and sodium butyrate. RESULTS: This multitherapy increased the survival rate and life quality, without overt toxicity, compared to the standard treatment for osteosarcomas. The agents in this approach have several functions. They exert antiproliferative, antiangiogenic, cytostatic, antioxidant, antimetastatic, and immunomodulating features. Moreover, the inclusion of ATRA, MLT, and sodium butyrate has reinforced antitumor properties on cancer stem cells. Furthermore, the non-cytolytic and non-cytotoxic metronomic hydroxyurea dosage increased the biological therapy outcome by strengthening antitumor capability. FINDINGS: This multitherapy approach is effective against osteosarcoma. INTERPRETATION: The multistrategy of this multitherapy therapy are inhibiting the proliferative-invasiveness and neoplastic angiogenesis, silencing the survival system of cancer stem cells, enhancing the immunomodulatory and antioxidant activities, improving vitality and efficiency of normal cells, and depressing the efficiency and vitality of neoplastic ones.