Objective This study aimed to explore the role and mechanism of circ0000781 in osteosarcoma(OS) proliferation by sponging miR-21-5p and regulating BTG2 expression and provide a novel therapeutic target for the OS. Methods QRT-PCR was used to detect the expression of BTG2 in OS cell lines. CCK8 was used to detect the proliferation ability of cells in each group. Transwell assay were performed to detect OS cells invasion ability. Biological database and luciferase reporter were performed to confirm the binding of BTG2 with miR-21-5p and miR-21-5p with circ0000781. Results BTG2 was lowly expressed in OS cell lines，and enforced-expression of BTG2 inhibited OS cell proliferation and invasion ability. miR-21-5p can target to bind BTG2 and negatively regulate BTG2 expression，and circ0000781 can target to bind miR-21-5p and down regulate miR-21-5p expression. overexpression of circ0000781 increased the expression level of BTG2. Conclusion BTG2 acts as a tumor suppressor gene in OS，circ0000781 inhibits osteosarcoma proliferation and invasion by sponging miR-21-5p and upregulating BTG2 expression.