Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.