Brain cancer is one of the most aggressive malignancies affecting the central nervous system (CNS), with glioblastoma multiforme (GBM) representing the most malignant and rapidly progressive form of glioma. The present study aimed to analyze the expression patterns of the proto-oncogenes EGFR and MAPK1 in glioma and evaluate their association with tumor progression and prognosis. The study was conducted using an in silico bioinformatics approach based on publicly available genomic datasets obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Gene expression analysis was performed using the UCSC Xena Browser platform, while Kaplan–Meier survival analysis was used to determine prognostic significance. The results demonstrated significant overexpression of EGFR and MAPK1 in glioma tissues compared with normal brain tissues. Expression levels of both genes progressively increased from low-grade glioma (LGG) to high-grade glioblastoma, indicating a strong association with tumor aggressiveness and malignancy. Approximately 50–60% of GBM cases showed EGFR overexpression, while elevated MAPK1 expression was associated with increased activation of the MAPK/ERK signaling pathway involved in tumor proliferation, invasion, angiogenesis, and survival. Survival analysis further revealed that high expression levels of EGFR and MAPK1 were associated with poor overall survival and unfavorable clinical prognosis in glioma patients. The findings suggest that dysregulation of EGFR and MAPK1 plays a critical role in glioma progression and highlights their potential significance as molecular biomarkers and therapeutic targets in brain cancer research.