Significance Glioblastoma (GBM) is the most lethal brain malignancy lacking effective treatment. In this study, we demonstrate that BCL6 is a prognostic marker and a targetable GBM-promoting factor. Silencing of BCL6 inhibits the malignant phenotype of GBM cells and triggers cellular senescence. We also identify AXL as an important BCL6 transcriptional target, the expression of which is also regulated positively by NCoR, a BCL6 cofactor. Either silencing of BCL6 or targeted disruption of the BCL6/NCoR complex diminishes AXL expression and inhibits GBM growth. This study elucidates a crucial BCL6-mediated signaling pathway in GBM biology. More importantly, our results highlight the promise and merit of targeting BCL6 for treating this deadly disease.