Tumor necrosis factor alpha-induced protein 8-like 3 (TIPE3) is closely related to tumourigenesis and development. However, its role in human glioblastoma (GBM) and the underlying mechanisms remain unclear. In this study, we demonstrate that TIPE3 is upregulated in GBM, and its high expression predicts poor prognosis. TIPE3 depletion induces GBM cell apoptosis both in vitro and in vivo. Mechanism studies reveal that TIPE3 inhibits p38 phosphorylation and negatively regulates the p38 MAPK pathway. TIPE3 associates with p38. The nuclear translocation of p38 is blocked by TIPE3 overexpression. And p38 phosphorylation could regulate TIPE3-mediated p38 nuclear-cytopalsmic translocation but does not affect TIPE3-p38 association. Rescue experiments confirm that TIPE3 inhibits GBM cell apoptosis via the p38 MAPK pathway. In conclusion, TIPE3 inhibits p38 phosphorylation and blocks p38 nuclear translocation. This action thus negatively regulates the p38 MAPK pathway and results in GBM cell survival.