Osteosarcoma is the most common primary malignant bone tumor in adolescents. While treatments for osteosarcoma have improved, the overall survival has not changed for three decades, and thus, new targets for therapeutic development are needed. Recently, glucocorticoids have been reported to have antitumor effects. Mometasone furoate (MF), a synthetic glucocorticoid, is of great value in clinical application, but there are few reports on its antitumor effect. Here, we verified the effect of MF on osteosarcoma in vitro and in vivo. In vitro, cell proliferation, cell cycle progression, apoptosis and cell metastasis were detected using Cell Counting Kit-8 (CCK8), colony formation, flow cytometry, wound-healing and transwell assays, respectively. In vivo, we generated a xenograft mouse model. To examine the potential role of the AMPK pathway, an AMPK-specific inhibitor (dorsomorphin) was used. The expression levels of factors related to the cell cycle, apoptosis and activation of the AMPK/mTOR pathway were assessed by immunohistochemistry and Western blotting. MF inhibited proliferation and metastasis and induced S phase arrest and apoptosis in osteosarcoma cells in a dose-dependent manner. In vivo, MF effectively inhibited osteosarcoma cell growth and pulmonary metastasis; however, it had no negative effect on the internal organs. Additionally, MF could activate the AMPK/mTOR pathway in osteosarcoma. Dorsomorphin significantly attenuated MF-induced antitumor activities. In summary, MF can inhibit osteosarcoma proliferation and metastasis and promote osteosarcoma cell apoptosis through the AMPK/mTOR signaling pathway in vitro and in vivo, which can provide a new rationale for subsequent academic and clinical research on osteosarcoma treatment.