Glioblastoma represents a highly aggressive form of malignant tumor within the central nervous system. Although chemotherapy remains the primary therapeutic strategy, its efficacy is often limited. To overcome the limitations associated with chemotherapeutic agents, such as high toxicity and non-specific adverse effects, a novel nanoparticle system comprising cRGD-modified and glutathione (GSH)-responsive polymers, and PEG-ss-Dox and apatinib (AP) (PDOX-AP/cRGD-NPs) is developed. PDOX-AP/cRGD-NPs show effective penetration of the blood-brain barrier (BBB), facilitate targeted delivery to brain tumors, and exhibit controlled drug release. PDOX-AP/cRGD-NPs show more effect in reducing the viability of GL-261, U87-MG, and LN-229 cells, inhibiting clonogenicity, and suppressing anti-apoptotic protein expression than PDOX/cRGD-NPs or AP/cRGD-NPs. Additionally, PDOX-AP/cRGD-NPs substantially increase drug uptake, BBB penetration, apoptosis rates, and the proportion of cells in the G2 phase. In vivo experiments further reveal that cRGD-directed nanoparticles exhibit superior accumulation in glioma regions compared to their non-cRGD-modified counterparts. In the interim, PDOX-AP/cRGD-NPs demonstrate significant efficacy in suppressing both ectopic and orthotopic growth of GL-261 gliomas, as well as orthotopic LN-229 gliomas, thereby markedly extending the median survival duration. This study introduces a promising targeted co-delivery system for combination chemotherapy.© 2025 Wiley‐VCH GmbH.