Background Glioma, a common primary brain tumor arising from glial cells, presents significant therapeutic challenges due to its diverse and complex biological behavior. While disulfidptosis has recently emerged as a novel form of cell death, the role of disulfidptosis-related genes (DRGs) in glioma and their relationship with the tumor immune microenvironment remains poorly understood. Methods We analyzed DRGs expression patterns in glioma samples and their correlation with patient survival using data from TCGA, GEO, and CGGA databases. We employed ROC curve analysis to evaluate the diagnostic potential of individual DRGs and identify hub genes. We investigated the relationship between hub gene expression and immune cell infiltration through immune infiltration analysis. Additionally, we conducted drug sensitivity analysis and molecular docking to explore associations between hub gene expression and drug responsiveness. Finally, we validated DRGs expression in glioma samples using RT-PCR and tissue microarrays. Results Among the ten DRGs examined, six genes (OXSM, SLC3A2, RPN1, NDUFS1, GYS1, and LRPPRC) showed significant differential expression in glioma tissues, while four (NCKAP1, NDUFA11, NUBPL, and SLC7A11) did not. Survival analysis revealed that elevated expression of OXSM, RPN1, GYS1, SLC3A2, and NDUFA11 correlated with poor patient outcomes. ROC analysis of both TCGA test and GEO validation sets identified OXSM as a hub gene, with AUC values exceeding 0.88. CGGA database analysis demonstrated higher OXSM expression in GBM compared to LGG, with peak expression in WHO grade IV tumors, significantly correlating with reduced overall survival (p < 0.01). Immune infiltration analysis showed that OXSM expression correlated with various immune cell populations, particularly significantly positively correlated with macrophages M0, M2, and T cells gamma delta, and significantly negatively correlated with monocytes. Drug sensitivity analysis indicated that high OXSM expression enhanced sensitivity to several therapeutic agents. RT-PCR and tissue microarray analyses confirmed elevated OXSM expression in high-grade gliomas. Conclusion Our study identifies OXSM as a key DRG hub gene in glioma, with elevated expression strongly correlating with poor patient prognosis. The observed relationship between OXSM expression and immune cell infiltration suggests its potential role in modulating the glioma microenvironment. These findings advance our understanding of glioma’s molecular mechanisms and may inform the development of novel therapeutic strategies.