CSN5, a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), functions as a potential tumor promoter in various cancers. However, the biological functions and clinical significance of CSN5 in osteosarcoma (OS) remains unclear. Here, we report that OS tumors overexpressed CSN5 compared with normal bone tissues, and CSN5 overexpression was obviously associated with the malignant phenotype and poor prognosis in patients with OS. In addition, high CSN5 expression significantly promoted the growth of OS cells, whereas CSN5 silence suppressed the tumorigenicity of OS cells. Furthermore, we found PI3K/Akt signaling pathway contributed to the effects of CSN5 in OS cells, and blocking the Akt pathway significantly inhibited the actions of CSN5. Mechanistically, we demonstrate that CSN5 positively regulated EGFR stability through reducing the levels of EGFR ubiquitination, thereby activating the PI3K/Akt signaling pathway in OS cells. Moreover, our results shown that the oncogenic effects of CSN5 on OS cells were EGFR dependent. Thus, CSN5 has a central role in regulating diverse aspects of the pathogenesis of OS, which could be a potential diagnostic and therapeutic target for OS.