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TNFAIP8, a cytosolic TNF-α-inducible oncogenic molecule, plays pivotal roles in many types of cancers. However, the effect of TNFAIP8 on glioma remains elusive. In this study, we confirmed that TNFAIP8 promoted glioma viability and motility through alteration of nucleotide metabolism and tricarboxylic acid (TCA) cycle. Firstly, bioinformatic analysis indicated that TNFAIP8 expression elevated along with the WHO grade and predicted adverse prognosis in gliomas. Moreover, TNFAIP8 was enriched in gliomas with progressive genotypes, serving as an efficient indicator for mesenchymal glioma. To determine its function in glioblastoma progression, cell viability, migration and invasion were examined by loss/gain of function experiments. TNFAIP8 promoted glioma proliferation, migration, invasion and transition to mesenchymal phenotype. These findings were further confirmed in vivo. RNA sequencing and liquid chromatography-mass spectrometry (LC-MS) results showed impaired nucleotide metabolism and TCA cycle after TNFAIP8 knockdown, implying that TNFAIP8 enhanced glioblastoma progression via metabolic dysfunction. In summary, this study identified a novel oncogene in glioma with great potential for prognostic prediction and subtype identification. Alterations in metabolic process and transition towards mesenchymal subtype were supposed to be the underlying mechanisms for the oncogenic function of TNFAIP8.