It is still a controversy whether the role of Sirtuin 7 (SIRT7) is an oncogene or a tumor suppressor gene in cancer as SIRT7 may have different functions in different types of cancer. Particularly, the specific roles of SIRT7 in the progression of osteosarcoma remain undiscovered. The main aim of this study is to identify the expression of SIRT7 in osteosarcoma and explore the biological functions of SIRT7 in regulating cellular processes of osteosarcoma cells. Here, we show that SIRT7 expression was significantly higher in osteosarcoma tissues and osteosarcoma cell lines than in non-tumor tissues and an immortalized normal cell line, respectively. Moreover, elevated SIRT7 levels in clinical samples indicate a poor prognosis of osteosarcoma patients. SIRT7 knockdown reduces proliferation, migration, invasion, tumor formation, and metastasis of osteosarcoma cells, while SIRT7 overexpression has the opposite effects. Mechanistically, SIRT7 down regulates H3K18ac expression and decreases H3K18ac binding to the promoter region of CDC4, leading to the inhibition of CDC4 transcription. Furthermore, the silencing of CDC4 partially rescued SIRT7 knockdown-mediated inhibitory effects on proliferation, migration, and invasion of osteosarcoma cells. In summary, our results show that SIRT7 promotes proliferation, migration, and invasion of osteosarcoma cells through targeting CDC4, suggesting a potential therapeutic target for SIRT7 based therapy for osteosarcoma.