Significance Glioblastoma is a highly lethal form of brain cancer with no current treatment options that substantially improve patient outcomes. A key therapeutic challenge is the identification of methods that reduce tumor burden while leaving normal cells unaffected. We show that TERT -promoter mutations, common in glioblastoma, lead to TERT reactivation through increased binding of GABPB1L-isoform–containing transcription factor complexes. In turn, we find that cancer-cell–specific inhibition of TERT through GABPB1L reduction results in near-term anti-growth effects and an impaired DNA damage response that profoundly increase the sensitivity of glioblastoma tumors to frontline chemotherapy. Our results thus provide rationale for GABPB1L inhibition combined with temozolomide chemotherapy treatment as a promising therapeutic strategy for glioblastoma.