In the present study, we provide scientific rationale for the clinical application of ZOL as a radiosensitizer in osteosarcoma (OS) by evaluating the effects of single and combined treatments on OS cell survival, apoptosis, cell cycle regulation, DNA repair activity, PI3K-Akt and MAPK signaling, and tumor cell invasiveness/EMT markers in vitro, in vivo, and in a patient sample. Here, AKT1 is linked to osteosarcoma.