Glioblastoma (GBM) is the most common malignant primary brain tumor, with an overall median survival of less than two years after resection. The urgent goal in pre-clinical investigations is to develop effective therapeutic strategies to prolong the GBM patients’ survival and improve the poor prognosis. Although various inorganic nanoplatforms have been applied in GBM treatment, they still face obstacles such as poor brain targeting, low tumor effective penetration, and serious monotherapy resistance. Here, we designed an environmental-dependent tumor-killing nanoreactor (RFcAD) with a gold-ferri nanoagglomerates form structure that effectively inhibits GBM proliferation via catalyzing reactive oxygen species (ROS) generation, exhausting glucose, and NIR-based photothermal therapy. With iRGD decoration, RFcAD can effectively penetrate the blood–brain barrier and target GBM. The “bomb-like” structured RFcAD exhibited a glutathione (GSH)-responsive release of toxicity agent DM1 and pH-dependent nanoagglomerates degradation with gold particles and superparamagnetic iron oxide nanoparticles (SPIONS) release. Gold particles and SPIONS destroy GBM cells as chemodynamic therapy agents via exhibiting a glucose oxidase (GOx)-like and peroxide (POx)-like catalytic ability to generate cytotoxic ROS and exhaust intracellular glucose, respectively. Synergistic with DM1-based chemotherapy and NIR-induced photothermal therapy, RFcAD can significantly reduce GBM proliferation both in vitro and in vivo. This work highlights that the RFcAD nanoreactor can benefit GBM inhibition by improving tumor targeting, tissue penetration, and cytotoxicity.