Glioblastoma (GBM) is an aggressive brain tumor characterized by molecular complexity and resistance to conventional treatments, including surgery, radiation, and chemotherapy. Despite these challenges, advancements in receptor tyrosine kinase (RTK) research, combined with multi-omics approaches, hold promise for improving patient outcomes and survivability. RTKs are central to GBM progression, influencing cell proliferation, survival, and angiogenesis. However, the complexity of RTK signaling necessitates a broader, integrative perspective, which has been enabled by the emergence of -omics sciences. Multi-omics technologies-including genomics, transcriptomics, proteomics, and metabolomics-offer unprecedented insights into the molecular landscape of GBM and its RTK-driven pathways. Genomic studies have revealed mutations and amplifications in RTK-related genes, while transcriptomics has uncovered alterations in gene expression patterns, providing a clearer picture of how these aberrations drive tumor behavior. Proteomics has further delineated changes in protein expression and post-translational modifications linked to RTK signaling, highlighting novel therapeutic targets. Metabolomics complements these findings by identifying RTK-associated metabolic reprogramming, such as shifts in glycolysis and lipid metabolism, which sustain tumor growth and therapy resistance. The integration of these multi-omics layers enables a comprehensive understanding of RTK biology in GBM. For example, studies have linked metabolic alterations with RTK activity, offering new biomarkers for tumor classification and therapeutic targeting. Additionally, single-cell transcriptomics has unveiled intratumoral heterogeneity, a critical factor in therapy resistance. This article highlights the transformative potential of multi-omics in unraveling the complexity of RTK signaling in GBM. By combining these approaches, researchers are paving the way for precision medicine strategies that may significantly enhance diagnostic accuracy and treatment efficacy, providing new hope for patients facing this devastating disease.