Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT ₂ R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT ₂ R. We repurposed EMA401, an AT ₂ R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT ₂ R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT ₂ R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT ₂ R differ drastically from complexes of AT ₂ R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2–tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.