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Background: Glioblastoma (GBM) represents the most malignant glioma among astrocytomas and is a lethal form of brain cancer. Many RAB genes are involved in different cancers but <i>RAB42</i> (Ras-associated binding 42) is seldom studied in GBM. Our study aimed to explore the role of <i>RAB42</i> expression in the development and prognosis of GBM. Methods: All GBM patient data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The relevance of <i>RAB42</i> expression to the clinicopathologic characteristics of GBM patients was analyzed. The overall survival (OS) significance was determined using log-rank. Significantly enriched KEGG pathways were screened using gene set enrichment analysis (GSEA). Results: High expression of <i>RAB42</i> was observed in GBM specimens compared with normal samples, which was also verified in cell lines and tissue samples. Elevated <i>RAB42</i> expression was correlated with higher GBM histological grade. The prognosis of GBM patients with high <i>RAB42</i> expression was worse than those with lower <i>RAB42</i>. A total of 35 pathways, such as the P53 pathway, were significantly activated in highly <i>RAB42</i>-expressed GBM samples. Conclusions: High <i>RAB42</i> expression is related to the development of GBM, and <i>RAB42</i> is a probable prognostic marker for GBM.