Glioblastoma is a highly malignant type of central nervous system tumor. In the present study, the results of RNA sequencing indicated that cAMP responsive element binding protein 3 (CREB3) was upregulated in tumor tissues from patients with GBM. The cAMP responsive element binding protein 3 (CREB3) pathway is a major contributor to the malignant progression of glioblastoma. In this study, we explored the mechanisms by which CREB3 regulates the proliferation, invasion and apoptosis of glioblastoma. Pairs of glioblastoma and normal tissues were subjected to RNA sequencing. Then, qRT-PCR and Western blotting were used to detect CREB3 levels in glioblastoma tissues and cell lines, respectively. CREB3 was upregulated in glioblastoma tissues and cell lines. Overexpression of CREB3 promoted the proliferation and invasion of SHG-44 cells, while downregulation of CREB3 inhibited the invasion of U251MG cells. Knockdown of CREB3 also induced apoptosis in U251MG cells and increased the protein levels of BAX, active caspase 3, p-PERK, p-eIF2α and ATF4. An in vivo study in nude mice bearing U251MG cell xenografts confirmed these results. Our findings indicate that CREB3 functions as a tumor promoter in glioblastoma, and thus could serve as a treatment target in glioblastoma patients.