Glioblastoma (GBM) is foremost the most aggressive primary brain tumor, presenting extensive therapeutic challenges due to its high invasiveness, genetic complexity, and resistance to established treatments. Despite substantial advances in surgical and chemotherapeutic interventions, the median survival rate for patients is only 14.6 months, and the prognosis remains poor. This review focuses on the molecular hallmarks of GBM, including the activation of the PI3K/Akt pathway, genomic instability, and the deregulation of epidermal growth factor receptor (EGFR), all of which contribute to the tumor's aggressive behavior. Current therapies, such as Temozolomide and Bevacizumab, have limitations, highlighting the need for novel treatment strategies. Phytochemicals, bioactive compounds found in plants, have emerged as potential therapeutic agents by targeting multiple cellular pathways involved in GBM progression. This review provides an overview of key phytochemicals, including quercetin, curcumin, apigenin, and resveratrol. These compounds have shown promise in preclinical studies, with their anti-invasive, anti- angiogenic, pro-apoptotic, and anti-proliferative properties positioning them as strong candidates for GBM therapy. While phytochemicals offer a promising avenue for GBM treatment, further research is required to fully understand their mechanisms of action and to evaluate their efficiency in clinical settings. Developing multi-targeted, safer, and cost-effective anti-GBM therapies could significantly improve patient outcomes.