Current therapeutic strategies against glioblastoma multiforme (GBM) are futile mainly because of the poor access of drugs into malignant tissues, which is hindered by the tight blood-brain tumor barrier in the GBM vasculature. Nanomedicines have shown potential for circumventing the vascular barriers of GBM, particularly by targeting markers on the luminal side of endothelial cells in the blood vessels of GBM for achieving effective and selective translocation into the tumor. Thus, as the αvβ3 and αvβ5 integrins overexpressed on the endothelial cells of GBM can be targeted by cyclic-Arg-Gly-Asp (cRGD) peptide, herein, we developed cRGD-installed micellar nanomedicines loading epirubicin, the potent antiglioblastoma agent, through a pH-sensitive hydrazone-bond for effective treatment of GBM. These cRGD-installed epirubicin-loaded polymeric micelles (cRGD-Epi/m) achieved faster and higher penetration into U87MG cell-derived 3D-spheroids than the micelles without cRGD, conceivably through a cRGD-integrin mediated pathway. In vivo, the cRGD-installed micelles effectively suppressed the growth of an orthotopic GBM model by delivering high levels of epirubicin throughout the tumor tissue. These results indicate significant prospects for cRGD-Epi/m as an effective and translationable treatment against GBM.