Background <p>Glioblastoma (GBM), classified as a WHO grade IV tumor, is associated with an extremely poor prognosis. Recent studies have identified NCOA4 as a crucial protein involved in ferritinophagy-induced ferroptosis. This research aims to investigate the clinical significance of NCOA4 in GBM.</p> Methods <p>The associations between NCOA4 and WHO grading, histology, clinicopathological characteristics, and prognosis were examined using the TCGA-GBMLGG, CGGA, and TCGA-GBM datasets, complemented by immunohistochemical experiments. Subsequently, the prognostic significance of NCOA4 was assessed through univariate and multivariate Cox regression analyses using the TCGA-GBM dataset. Moreover, the associations between NCOA4 and various infiltrating immune cells as well as their markers in GBM were investigated. Ultimately, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were utilized to elucidate the biological roles of NCOA4.</p> Results <p>NCOA4 expression significantly decreased with increasing WHO grade and malignancy of gliomas (<i>p</i> &lt; 0.05), reaching the lowest levels in GBM (<i>p</i> &lt; 0.05), indicating its potential diagnostic value. Low NCOA4 expression was significantly tied to a poor prognosis in GBM (<i>p</i> &lt; 0.05) and functioned as an independent prognostic indicator (<i>p</i> &lt; 0.05). It was also related to inadequate infiltration of B cells, macrophages, neutrophils, and dendritic cells (<i>p</i> &lt; 0.05). Insufficient infiltration of B cells and macrophages could forecast a poor prognosis in GBM (<i>p</i> &lt; 0.05). GO and KEGG analyses further confirmed NCOA4’s involvement in ferroptosis and B cell signaling regulation pathways (<i>p</i> &lt; 0.05).</p> Conclusions <p>NCOA4’s low expression in GBM correlates with tumor malignancy, adverse outcomes, and inadequate immune cell infiltration, suggesting its potential as a therapeutic target.</p>