Nidogen-2 (NID2) is a critical component of the extracellular matrix (ECM), which plays a regulatory role in cell adhesion, migration, differentiation, and survival. Previous studies have shown that NID2 is deregulated in several types of cancer, but its role in glioma is unknown. The present study investigated the prognostic value of NID2 in glioma and its associated molecular pathways and functional roles in malignant progression. The performed analyses included investigating the NID2 expression profile using the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and tumor tissue microarray. The findings demonstrated that NID2 high expression predicts worse patient survival by both univariable and multivariable analyses. There is a strong correlation between NID2 upregulation and tumor grade. In stably NID2-overexpressed glioma cells, RNA-Seq analysis revealed coactivation of oncogenic functional pathways, including cell proliferation, survival, epithelial–mesenchymal transition, ECM organization, and migration. Overexpression of NID2 in U87MG and T98G cells promoted cell proliferation, migration, and invasion. TUNEL assay showed NID2 overexpression protected cells from apoptosis. Western blotting analysis showed activation of Akt and Bcl-xL in NID2-overexpressed cells. Our results show that NID2 is a promising prognostic marker in glioma.