Glioblastoma (GBM) remains a highly aggressive and lethal brain tumor, primarily due to the blood-brain barrier (BBB), tumor heterogeneity, and treatment-resistant stem cells. Nanoparticles (NPs) have emerged as a promising approach to overcome these challenges by attaching targeting ligands to enhance therapeutic efficacy. Peptides, due to their ease of synthesis and high selectivity, are particularly prominent among these ligands. This review critically examines single and multiligand strategies for peptide-functionalized NPs in GBM therapy, highlighting their potential in integrating external stimuli, biomimetic approaches, and nanocatalytic medicine. It also discusses alternative routes of administration, such as nose-to-brain delivery and local treatment within the resected tumor cavity. The review covers the latest advancements in peptide-functionalized NPs, including their ability to target multiple receptors, enhance drug delivery, and improve therapeutic efficacy. Additionally, it explores the integration of external stimuli like magnetic fields, hyperthermia, and photothermal therapy to further enhance the effectiveness of GBM treatments. The review concludes by discussing significant obstacles and potential strategies to overcome them, providing a comprehensive perspective on this promising field of GBM therapy.Glioblastoma (GBM) remains a highly aggressive and lethal brain tumor, primarily due to the blood-brain barrier (BBB), tumor heterogeneity, and treatment-resistant stem cells. Nanoparticles (NPs) have emerged as a promising approach to overcome these challenges by attaching targeting ligands to enhance therapeutic efficacy. Peptides, due to their ease of synthesis and high selectivity, are particularly prominent among these ligands. This review critically examines single and multiligand strategies for peptide-functionalized NPs in GBM therapy, highlighting their potential in integrating external stimuli, biomimetic approaches, and nanocatalytic medicine. It also discusses alternative routes of administration, such as nose-to-brain delivery and local treatment within the resected tumor cavity. The review covers the latest advancements in peptide-functionalized NPs, including their ability to target multiple receptors, enhance drug delivery, and improve therapeutic efficacy. Additionally, it explores the integration of external stimuli like magnetic fields, hyperthermia, and photothermal therapy to further enhance the effectiveness of GBM treatments. The review concludes by discussing significant obstacles and potential strategies to overcome them, providing a comprehensive perspective on this promising field of GBM therapy.