: Osteosarcoma is considered as one of the most common types of bone tumors occurs among adolescents and children. Current therapy strategies still have limited effectiveness; therefore, the development of new therapies is urgent. Morusin is a compound isolated from Morus australis (Moraceae). Many studies have reported its anti-tumor effect on several tumor types. However, its role in osteosarcoma is still unclear. In this study, we determined that morusin significantly suppresses the proliferation of osteosarcoma cells. Morusin also promotes the apoptosis of osteosarcoma cells. Furthermore, the migration and invasion of osteosarcoma were reduced after exposure to morusin. The deep mechanism was determined to be the inhibition of the PI3K/AKT signaling pathway. In conclusion, our study indicates morusin as a potential candidate for osteosarcoma therapy.