Background: Glioblastoma is one of the most malignant tumors in the brain with high mortality. In recent years, immunotherapy and targeted therapy show great prospects in the treatments for glioblastoma, whereas more effective therapeutic targets are still urgently needed to be developed. Nucleobindin-2 (NUCB2) is the precursor protein of nesfatin-1, which have a variety of metabolic functions, such as food intake and temperature regulation. In recent years, the potential link between NUCB2 and the development of multiple cancer was gradually revealed; however, the effects of NUCB2 on the progression of glioblastoma are still unclear. Methods: Immunohistochemical assays were performed to explore the NUCB2 expression levels in 94 samples of glioblastoma and corresponding nontumor tissues; patients were divided into NUCB2 high expression group and low expression group. Clinical analysis related to the clinical features, the potential link between NUCB2 expression levels, and clinical features were analyzed; the effects of NUCB2 on cell proliferation and invasion of glioblastoma were detected through colony formation and MTT assay, and transwell assay respectively. The possible effects of NUCB2 on tumor growth and metastasis were measured in mice. Results: In this study, we demonstrated that NUCB2 over-expression was correlated with the high degree of recurrence of patients with glioblastoma. Further, we also revealed that NUCB2 promoted cell proliferation and invasion of glioblastoma in vitro and promoted the growth and metastasis of glioblastoma in mice. Conclusion: This study provided evidence that NUCB2 might be a novel therapeutic target of glioblastoma.