In this study, we determined the underlying molecular mechanisms of a novel function for AMBN in osteosarcoma; stable overexpression of AMBN inactivated the Src-Stat3 axis and subsequently induced caspase-3 mediated apoptosis and sensitivity to doxorubicin, while inhibiting colony formation, cell migration, tumor growth and pulmonary metastases. Here, SRC is linked to osteosarcoma.