Background <p><?tk 3?>Glioblastoma (GBM) is the most aggressive primary brain tumor, with poor responsiveness to existing therapies and no established second-line treatment for recurrence. Boron neutron capture therapy (BNCT) has emerged as a promising modality that delivers selective cytotoxicity to recurrent GBM, yet its efficacy is constrained by tumor-intrinsic DNA repair mechanisms. Targeting DNA repair pathways may therefore represent a rational strategy to potentiate BNCT and improve outcomes in TMZ-resistant GBM.</p> Methods <p><?tk 3?>We investigated whether combining BPA-mediated BNCT with the PARP inhibitor olaparib enhances efficacy in temozolomide (TMZ)-resistant U-87 TR and parental U-87 MG GBM cells. Clonogenic assays were used to quantify cytotoxicity, while mechanistic studies evaluated DNA damage, cell cycle arrest, and apoptosis.</p> Results <p><?tk 3?>Olaparib significantly sensitized GBM cells to BNCT, reducing survival to 40.7 ± 8.1% in U-87 MG and 24.2 ± 8.3% in U-87 TR cells, with radiation enhancement ratios of 1.53 and 1.95, respectively. In U-87 TR cells, the combination treatment induced persistent γH2AX foci, sustained G₂/M arrest, and suppressed BNCT-driven upregulation of BRCA1 and RAD51, indicating impaired HR repair. Apoptosis was markedly increased in both cell lines, proceeding through PUMA–BAX activation in U-87 MG and via PUMA-independent pathways in U-87 TR.</p> Conclusions <p><?tk 3?>PARP inhibition (Olaparib) enhances BNCT-induced DNA damage, disrupts HR repair, and induces apoptosis through distinct mechanisms in sensitive and resistant GBM cells. These findings provide mechanistic evidence for BNCT–PARP inhibitor combinations as a strategy to overcome therapeutic resistance and merit further translational and clinical investigation in TMZ-resistant GBM.</p> Graphical abstract <p></p>