Glioma is the most common adult malignant primary brain tumor; however, the effect of chemotherapy is often limited by drug‑resistance and poor prognosis is common. Ring finger protein 138 (RNF138) belongs to the E3 ligase family, and has significantly higher expression level in glioma tissue than in noncancerous brain tissues. Epithelial-mesenchymal-transition (EMT) has a critical role in cancer invasion and metastasis, ultimately leading to increased cell motility and resistance to genotoxic agents. Extracellular‑signal regulated kinase (Erk) pathways promote the growth of glioma cells and enhance tumor invasion, with a role in the progression of EMT. However, the association between RNF138 and human glioma progression remains poorly understood. Relatively little is known about the association between RNF138, Erk, and EMT in glioma progression. In the current study, experiments were performed to explore the potential roles and mechanisms of RNF138 in glioblastoma in vitro and in vivo. Glioma cell line proliferation, migration and invasion were inhibited by knockdown of RNF138 in vitro. By lowering the RNF138 expression, cleaved caspase3 and E‑cadherin were upregulated, while phospho‑Erk1/2, vimentin, MMP2, HIF‑1α and VEGF were downregulated in U87 and U251 cells in vitro. In vivo findings revealed that the growth of U87 cell‑transplanted tumors in nude mice was inhibited in tumors with RNF138 knockdown. These findings suggested that downregulation of RNF138 inhibited glioma cell proliferation, migration, and invasion, and reversed EMT, potentially via Erk signaling pathway. Therefore, RNF138 may be a potential therapeutic target against glioma.