Glioblastoma(GBM) is the most common malignant brain cancer in adults, affecting 14,000 people in the U.S. and 50,000 people worldwide per year. The disease is incurable, with a median survival of less than 5% at five years, highlighting a desperate need for new therapeutic strategies. OLIG2 is a basic helix-loop-helix (bHLH) transcription factor that is expressed in neural progenitor cells during embryonic development where it sustains their replication-competent state and regulates their oligodendrocyte and motor neuron multi-lineage potential. In GBM, OLIG2 is re-expressed at high levels and drives an oncogenic program that leads to dysregulation of the cell cycle and subsequent gliomagenesis. This central role for OLIG2 in GBM initiation and growth, along with its low expression in normal tissues, identifies OLIG2 as a target for GBM therapy. Here we report the characterisation of an orally bioavailable small-molecule OLIG2 inhibitor, CT-179, the first bHLH transcription factor targeting drug developed for the treatment of cancer. The drug is well tolerated and easily penetrates the blood brain barrier, where it reduces brain tumour burden in orthotopic mouse and zebrafish avatar models. Mechanistically, CT-179 displayed nanomolar anti-proliferative activity and induced significant apoptosis mediated through disruption of the cell cycle that resulted in mitotic catastrophe at prometaphase. CT-179 showed enhanced anti-tumour activity in mouse models of GBM when used in combination with standard of care radiotherapy and temozolomide. These studies demonstrate that the pharmacological inhibition of OLIG2 is an effective treatment strategy for GBM that warrants rapid translation into the clinic.