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Oxaliplatin is a member of the platinum group that is often used to treat glioma, a common type of malignant brain tumor, though it does not come with desirable and notable effects. This study attempted to investigate how ELK3 impacts the oxaliplatin resistance of glioma cells and its molecular mechanism. Bioinformatics analysis was employed to screen mRNAs with differential expression in glioma cells and predict the possible regulator downstream. We used qRT-PCR to detect the expression of ELK3 and RNASEH2A. Dual-luciferase and ChIP assays were adopted to reassure the regulatory relationship between the two. We also evaluated cell viability and sphere formation efficiency through CCK-8 and sphere formation assay and calculated the IC50 value by using CCK-8 assay. The expression of stemness-related proteins (ALDH1 and Nanog) was assessed through western blot. Glioma cells and tissues presented a significantly high expression of ELK3, the knock-down of which would reduce the cell viability, stemness and oxaliplatin resistance dramatically. Bioinformatics analysis predicted RNASEH2A to be the downstream regulator of ELK3. RNASEH2A was remarkably upregulated in glioma tissue and cells. The results from dual luciferase assay and ChIP experiment verified the binding relationship between RNASEH2A promoter region and ELK3. Then through rescue experiments, we confirmed that overexpression of RNASEH2A could compensate for the inhibition of glioma cell progression resulting from the knock-down of ELK3. ELK3 could promote stemness and oxaliplatin resistance of glioma cells by upregulating RNASEH2A, indicating that targeting ELK3/RNASEH2A axis may be a possible solution to overcome oxaliplatin resistance of glioma cells. [ABSTRACT FROM AUTHOR]