Leucine proline-enriched proteoglycan 1 has been extensively explored because of its protective function in cell homeostasis and correlation with osteogenesis imperfect. Human osteosarcoma is the most common primary malignant tumor of bone with multiple and complex genomic aberrations. However, the functional role of leucine proline-enriched proteoglycan 1 is still unknown in osteosarcoma. Thus we performed this study to explain the leucine proline-enriched proteoglycan 1 effect in osteosarcoma. Gene arrays of human osteosarcoma were downloaded from the Gene Expression Omnibus database. Quantitative real-time PCR was conducted to assess the expression of leucine proline-enriched proteoglycan 1 in osteosarcoma cell lines. Then we attenuated leucine proline-enriched proteoglycan 1 expression in MG63 cells by siRNA strategy and assessed the effect of leucine proline-enriched proteoglycan 1 on cell proliferation, migration and invasion through in-vitro experiments. Additionally, we detected the role of leucine proline-enriched proteoglycan 1 knockdown on PI3K/AKT pathway-related proteins using western blotting. Leucine proline-enriched proteoglycan 1 was increased in osteosarcoma tissues and cells. The overall survival curve demonstrated that high-regulated leucine proline-enriched proteoglycan 1 was linked with poor prognosis of patients with osteosarcoma. The capabilities of proliferation, migration and invasion were all inhibited in MG63 cell because of the downregulation of leucine proline-enriched proteoglycan 1. Furthermore, the expression of phosphorylated PI3K and AKT was impaired after knockdown the leucine proline-enriched proteoglycan 1 as well as P70S6K. In conclusion, leucine proline-enriched proteoglycan 1 might function as an important therapeutic factor in human osteosarcoma through regulating the PI3K/AKT signaling pathway.