Glioblastoma is one of the most malignant forms of cancer, for which no effective targeted therapy has been found. Although The Cancer Genome Atlas has provided a list of fusion genes in glioblastoma, their role in progression of glioblastoma remains largely unknown. To search for novel fusion genes, we obtained RNA‐seq data from TGS‐01 human glioma‐initiating cells, and identified a novel fusion gene (HMGA2‐EGFR), encoding a protein comprising the N‐terminal region of the high‐mobility group AT‐hook protein 2 (HMGA2) fused to the C‐terminal region of epidermal growth factor receptor (EGFR), which retained the transmembrane and kinase domains of the EGFR. This fusion gene product showed transforming potential and a high tumor‐forming capacity in cell culture and in vivo. Mechanistically, HMGA2‐EGFR constitutively induced a higher level of phosphorylated STAT5B than EGFRvIII, an in‐frame exon deletion product of the EGFR gene that is commonly found in primary glioblastoma. Forced expression of HMGA2‐EGFR enhanced orthotopic tumor formation of the U87MG human glioma cell line. Furthermore, the EGFR kinase inhibitor erlotinib blocked sphere formation of TGS‐01 cells in culture and inhibited tumor formation in vivo. These findings suggest that, in addition to gene amplification and in‐frame exon deletion, EGFR signaling can also be activated by gene fusion, suggesting a possible avenue for treatment of glioblastoma. What's new? Fusion genes are promising targets for the development of novel drug therapies against glioblastoma. Little is known, however, about their role in the disease. Here, a novel fusion gene, HMGA2‐EGFR, was identified from a human glioblastoma specimen containing glioma‐initiating cells (GICs). Forced expression of the HMGA2‐EGFR fusion protein induced transformation of NIH3T3 fibroblasts and, in glioblastoma cells, induced STAT5B phosphorylation, similar to the known EGFR mutant EGFRvIII. HMGA2‐EGFR overexpression also accelerated the growth of orthotopic U87MG tumors in mice, while the EGFR inhibitor erlotinib suppressed tumor formation by HMGA2‐EGFR‐expressing GICs and prolonged the survival of tumor‐bearing mice.