The deregulation of the epidermal growth factor receptor (EGFR) has a significant role in the progression of tumors. Despite the development of a number of EGFR-targeting agents that can arrest tumor growth, their success in the clinic is limited in several tumor types, particularly in the highly malignant glioblastoma multiforme (GBM). In this study, we generated and characterized EGFR-specific nanobodies (ENb) and imageable and proapoptotic ENb immunoconjugates released from stem cells (SC) to ultimately develop a unique EGFR-targeted therapy for GBM. We show that ENbs released from SCs specifically localize to tumors, inhibit EGFR signaling resulting in reduced GBM growth and invasiveness in vitro and in vivo in both established and primary GBM cell lines. We also show that ENb primes GBM cells for proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Furthermore, SC-delivered immunoconjugates of ENb and TRAIL target a wide spectrum of GBM cell types with varying degrees of TRAIL resistance and significantly reduce GBM growth and invasion in both established and primary invasive GBM in mice. This study demonstrates the efficacy of SC-based EGFR targeted therapy in GBMs and provides a unique approach with clinical implications.