Osteogenic sarcoma (OS) is a deadly skeletal malignancy whose cause is unknown. We report here a mouse model of OS based on conditional expression of the intracellular domain of Notch1 (NICD). Expression of the NICD in immature osteoblasts was sufficient to drive the formation of bone tumors, including OS, with complete penetrance. These tumors display features of human OS; namely, histopathology, cytogenetic complexity, and metastatic potential. We show that Notch activation combined with loss of p53 synergistically accelerates OS development in mice, although p53-driven OS is not Rbpj dependent, which demonstrates a dual dominance of the Notch oncogene and p53 mutation in the development of OS. Using this model, we also reveal the osteoblasts as the potential sources of OS. •Notch 1 intracellular domain induces bone tumors in mice with 100% penetrance•Mouse osteosarcoma initiated by Notch activation mimics the human disease•Notch activation and p53 loss independently and synergistically induce osteosarcoma•Committed osteoblasts are a potential source of tumor cells in osteosarcomagenesis Tao et al. show that Notch activation in osteoblasts is sufficient to initiate osteogenic sarcoma (OS)-like tumors that mimic human OS and demonstrate a dual dominance for Notch activation and p53 mutation in the development of OS.