Glioblastoma (GBM) is characterized by a severely hypoxic microenvironment that contributes to resistance against radiotherapy and chemotherapy. To address this challenge, we developed dual-functional manganese dioxide nanoparticles coated with polyacrylic acid (MnO₂–PAA NPs) capable of catalytically generating oxygen and delivering chemotherapeutic agents. These nanoparticles demonstrated excellent colloidal stability and reduced cytotoxicity compared to cationic formulations. In vitro studies confirmed their ability to reverse hypoxia in GBM cell lines and spheroid models, significantly enhancing the efficacy of ionizing radiation. Furthermore, MnO₂–PAA NPs were efficiently loaded with doxorubicin, achieving sustained drug release over 60 days. The combination of oxygen generation and chemotherapeutic delivery produced a synergistic cytotoxic effect, surpassing the impact of radiotherapy alone. This dual-modality approach offers a promising strategy to overcome hypoxia-driven resistance and improve therapeutic outcomes in glioblastoma.