Osteosarcoma (OS) is the most common primary bone malignancy because of its extra high tendency of metastasis. In-depth research is needed to uncover the pathogenesis of patients with OS cells. We collected 74 tissue samples from patients with OS cells and measured the expression levels of ghrelin by immunohistochemistry. Ghrelin was added into OS cell lines in CCK8 assays, JC-1 staining and Western blot analysis were performed to explore its effect on the aggressiveness of OS cells and drug resistance. To determine its function, ghrelin was overexpressed or knocked down in OS cells and then detect cell proliferation in the xenograft mouse model and orthotopic model. Western blot analysis was performed to explore ghrelin-regulated signal pathways. In this work, we identified the relation between the level of ghrelin expression and poor prognosis of OS patients. As well as promoting proliferation, migration, and invation, ghrelin promotes the survival of OS in vitro as well as in vivo, and reduces the apoptosis of OS cells. What's more, ghrelin increases the resistance of cis-platinum by changing mitochondrial function and decreases the expression of MDR-1. Above all, these results demonstrated ghrelin exerts tumorigenic and metastatic effects and may be a potential therapeutic target.