Glioblastoma (GBM) has been regarded as one of the most deadly and challenging cancers to treat with extremely poor prognosis. The limited efficacy of current chemotherapies might be attributed to the presence of glioma stem cells (GSCs) as well as the difficulties in passing through the blood–brain barrier (BBB) and targeting tumor cells. Tumor-derived exosomes are emerging as novel and promising drug delivery systems. However, great concerns regarding the biosafety and BBB penetrability remain to be addressed. Herein, we have developed a simple and feasible strategy to engineer GBM cell-derived exosomes with improved biosafety termed “Exo@TDPs” to deliver the cargos of chemotherapeutic agents temozolomide (TMZ) and doxorubicin (DOX) into GBM tissues. Exo@TDPs decorated with angiopep-2 (Ang-2) and CD133-targeted peptides improve the capacity to penetrate the BBB and target tumor cells. Both in vitro and in vivo studies demonstrate that Exo@TDPs can cross the BBB, target GBM cells, penetrate into deep tumor parenchyma, and release the therapeutic cargos effectively. Synergistic delivery of TMZ and DOX by Exo@TDPs exerts therapeutic effects to suppress the tumor growth and prolong the survival time of orthotopic syngeneic mouse GBM models. These findings suggest that our developed Exo@TDPs loaded with chemotherapeutic drugs may bring new possibilities for the application of tumor cell-derived exosomes for brain tumor treatment.