Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor kB (NF-kB) activation showing enrichment of known NF-kB target genes. Inhibition of NF-kB by either depletion of IkB kinase 2 (IKK2), expression of a IkBaM super repressor, or using a NEMO (NF-kB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-kB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-kB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-kB activity or targeting of inducible NF-kB genes is an attractive therapeutic approach for GBM.