Abstract Glioblastoma is the most common type of malignant primary brain tumor and displays highly aggressive and heterogeneous phenotypes. The transcription factor STAT3 has been reported to play a key role in glioblastoma malignancy. Thus, discovering targets and functional downstream networks regulated by STAT3 that govern glioblastoma pathogenesis may lead to improved treatment strategies. In this study, we identified that poly(A)-specific ribonuclease (PARN), a key modulator of RNA metabolism, activates EGFR–STAT3 signaling to support glioblastoma stem cells (GSC). Functional integrative analysis of STAT3 found PARN as the top-scoring transcriptional target involved in RNA processing in patients with glioblastoma, and PARN expression was strongly correlated with poor patient survival and elevated malignancy. PARN positively regulated self-renewal and proliferation of GSCs through its 3′–5′ exoribonuclease activity. EGFR was identified as a clinically relevant target of PARN in GSCs. PARN positively modulated EGFR by negatively regulating the EGFR-targeting miRNA miR-7, and increased EGFR expression created a positive feedback loop to increase STAT3 activation. PARN depletion in GSCs reduced infiltration and prolonged survival in orthotopic brain tumor xenografts; similar results were observed using siRNA nanocapsule-mediated PARN targeting. Pharmacological targeting of STAT3 also confirmed PARN regulation by STAT3 signaling. In sum, these results suggest that a STAT3-PARN regulatory network plays a pivotal role in tumor progression and thus may represent a target for glioblastoma therapeutics. Significance: A positive feedback loop comprising PARN and EGFR–STAT3 signaling supports self-renewal and proliferation of glioblastoma stem cells to drive tumor progression and can be targeted in glioblastoma therapeutics.