Glioblastoma is the most common lethal malignant intracranial tumor with a low 5‐year survival rate. Currently, the maximal safe surgical resection, followed by high‐dose radiotherapy (RT), is a standard treatment for glioblastoma. However, high‐dose radiation to the brain is associated with brain injury and results in a high fatality rate. Here, integrated pharmaceutics (named D‐iGSNPs) composed of gold sub‐nanometer particles (GSNPs), blood‐brain barrier (BBB) penetration peptide iRGD, and cell cycle regulator α‐difluoromethylornithine is designed. In both simulated BBB and orthotopic murine GL261 glioblastoma models, D‐iGSNPs are proved to have a beneficial effect on the BBB penetration and tumor targeting. Meanwhile, data from cell and animal experiments reveal that D‐iGSNPs are able to sensitize RT. More importantly, the synergy of D‐iGSNPs with low‐dose RT can exhibit an almost equal therapeutic effect with that of high‐dose RT. This study demonstrates the therapeutic advantages of D‐iGSNPs in boosting RT, and may provide a facile approach to update the current treatment of glioblastoma. Multifunctionalized gold sub‐nanometer particles (D‐iGSNPs) are designed to sensitize radiotherapy against glioblastoma, which is modified with cyclopeptide iRGD and cell cycle regulator α‐difluoromethylornithine. With small size and iRGD modification, the D‐iGSNPs can easily penetrate through the blood‐brain barrier and target the glioma, which make radiotherapy more effective toward glioblastoma.