Glioblastoma multiforme (GBM) is an extremely aggressive and malignant tumor of the central nervous system in adults. Therefore, understanding its pathogenesis is urgently needed. This study aimed to investigate the role of long noncoding RNA (lncRNA) highly upregulated in liver cancer (HULC) in GBM. The levels of lncRNA HULC and proteins in PI3K/AKT pathway in GBM tissues were measured. Kaplan–Meier method was used to analyze the survival. An in-vivo tumor xenograft model in mice was constructed and monitored. In GBM SGH44 and U87 cells, the proliferation, migration, invasion, cell cycle and apoptosis, cellular expression of proteins in PI3K/AKT pathway, and that of lncRNA HULC and microRNA (miR)-128 were determined. The interactions between lncRNA HULC, miR-128, and tenascin-R (TNR) were verified. The result showed lncRNA HULC was an oncogene that can promote cell proliferation, migration, and invasion in human GBM tissue, orthotopic transplantation in mice, and GBM cell lines. LncRNA HULC was further confirmed to affect TNR expression via sponging miR-128 and activating the PI3K/AKT pathway to promote cell proliferation in GBM. LncRNA HULC can affect the expression of TNR protein, activate the PI3K/AKT pathway, promote GBM cell proliferation, migration, and invasion, and inhibit apoptosis mediated by miR-128.