The blood-brain barrier (BBB) is a natural protective semipermeable membrane that shields the central nervous system (CNS) from harmful substances in the bloodstream. While this barrier is essential for protecting the brain, it also presents significant challenges for therapy in treating brain tumor such as glioblastoma multiforme (GBM). This limitation is particularly relevant for most chemical drugs and biopharmaceuticals. They struggle to penetrate the BBB, making efficient delivery to the brain highly sought after. Inadequate drug delivery to the brain can reduce therapeutic effectiveness and lead to increased side effects due to accumulation in other organs and tissues, especially after systemic administration. Overcoming the challenges related to drug delivery would open new treatment options for GBM and other CNS diseases. Nanoparticle-based approaches are highly promising, potentially offering a safer and less invasive alternative to current treatment options. This review provides a summary of the structure of the BBB and the main cell types that contribute to its function, with a specific focus on the barrier’s relevance in GBM. It also examines strategies for crossing the BBB, current treatment options, and prospects for GBM therapies. It emphasizes the significance of efficient delivery across the BBB and the potential of nanoparticles in advancing improved GBM treatments. Additionally, it introduces versatile nanoparticle-based drug delivery systems, including organic, inorganic, and biologics-derived approaches.