Human glioma is a kind of common and fatal intracranial tumor. Therefore, exploring effective drug targets for glioma is the main task of basic and clinical research. This study investigated the role of ubiquitin protein ligase E3 module N-recognition 5 (UBR5) in glioma and the underlying mechanism. First, TCGA datasets were employed to analyze the expression of UBR5 in glioblastoma or normal tissues. Western blot assay was applied to examine the protein expression level of UBR5 in glioma or adjacent tissues and other cell lines. It was found that UBR5 was highly expressed in glioma tissues and cells. Then, we discovered that UBR5 accelerated the invasion, proliferation, and migration of transfected glioma cells by colony formation, immunofluorescence staining, transwell, and wound healing assays. Furthermore, Western blot analysis revealed that UBR5 promoted the epithelial-mesenchymal transformation of glioma cells and regulated the ECRG4/NF-ҡB pathway. Finally, animal experiments and IHC analysis suggested that UBR5 promoted tumor growth in U251-MG cell-injected mice. In conclusion, this study found that UBR5 promoted the migration and invasion of glioma cells by regulating the ECRG4/NF-ҡB pathway.