Background Inhibition of p38 MAPK signaling leads to glioblastoma multiform (GBM) tumorigenesis. Nevertheless, the molecular mechanism which induces the p38 MAPK signaling silent during GBM genesis is yet to be figured out. Identifying new factors which could regulate p38 MAPK signaling is important for tumor treatment. Methods Flow-cytometry, TUNEL assay, Immunofluorescence, JC-1 assays, as well as western blotting analysis were used to detect the apoptosis of GBM cells. The detection devices of autophagy levels in GBM cells were western blotting analysis, immunofluorescence of LC3B protein, LC3B puncture assays and transmission electron microscopy. The functions of these critical molecules are further confirmed by intracranial xenografts in nude mice as in vivo experiments. Tumor tissue samples and clinical information were used to identify the correlation between RND2 and p62, LC3B expression, survival time of patient, tumor volume in clinical patients. Results We found that small GTPase RND2 expression significantly increased in human glioblastomas by summarizing the data of TCGA database. Our study demonstrated that the RND2 function is as an endogenous repressor of the p38 MAPK phosphorylation complex. RND2 physically interacted with p38, decreasing p38 phosphorylation, therefore, p38 MAPK signaling activities were inhibited. The forced expression of RND2 repressed the p38 MAPK signaling, which inhibited glioblastoma cell autophagy and apoptosis in vitro and induced the xenograft mice’s tumor growth in vivo. The downregulation of RND2, nevertheless, enhanced p38 MAPK signaling activities and promoted glioma cell autophagy and apoptosis. The inhibition of p38 phosphorylation abolished RND2 deficiency-mediated GBM cell autophagy and apoptosis. Most important, our study found that the RND2 expression was inversely correlated with patient survival time and was positively correlated with tumor size, indicating that RND2 was an oncogene which predicts a poorer clinical outcome of patients. Conclusions Our findings revealed RND2’s new function in GBM genesis and offered mechanistic insights into the inhibitory effects of RND2 in regard of the p38 MAPK activation regulation.