Ubiquitin-specific protease 22 (USP22), a novel deubiquitinating enzyme, belongs to an extended family of proteins that have ubiquitin hydrolase activity. Recently, USP22 has attracted widespread attention because of its implication in carcinogenesis. However, there have been no studies, to our knowledge, investigating the expression of USP22 in osteosarcoma (OS) and its association with OS progression. In this study, we explored the role of USP22 in OS. We demonstrated that USP22 was highly expressed in OS tissue and cell lines. Downregulation of USP22 inhibited OS cell proliferation, invasion, and epithelial–mesenchymal transition (EMT) in vitro. In addition, downregulation of USP22 suppressed OS tumor growth and metastasis in vivo. We also found that the PI3K/Akt signaling pathway was involved in the tumor-promoting effect of USP22 on OS progression. Taken together, we suggest USP22 as a novel therapeutic target for OS.