Emerging literature indicates the essential roles of long noncoding RNA (lncRNA) in the osteosarcoma (OS). However, the regulatory function and mechanism of FOXD2-AS1 in the OS is still elusive. In present research, the level of FOXD2-AS1 was significantly up-regulated in the OS tissue and cell lines compared to corresponding controls. The aberrant high-expression of FOXD2-AS1 indicated the poor clinical prognosis of OS patients. Transcription factor HIF-1α could bind with the promoter region of FOXD2-AS1 to activate the transcription in OS cells. Functionally, the knockdown of FOXD2-AS1 could repress the malignant biological properties of OS cells in vitro and vivo, including proliferation, invasion, apoptosis and tumor growth. Mechanistically, FOXD2-AS1 inhibited the expression of p21 via interacting with EZH2 to silence p21 gene expression. Overall, we conclude that FOXD2-AS1, induced by transcription factor HIF-1α, acts as an oncogene in the OS tumorigenesis and FOXD2-AS1 interacts with EZH2 to silence p21 protein. This finding could provide a novel insight and potential therapeutic target for the OS.