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Glioblastoma (GBM), the most aggressive type of primary brain tumor in adults, is characterized by a poor prognosis and considerable resistance to current therapies. Traditional treatment approaches-surgery, radiation, and chemotherapy-offer few clinical benefits and are often linked to increased recurrence rates and significant adverse effects. This underscores the urgent need for novel therapeutic strategies. Targeting the transforming growth factor-beta (TGF-β) signaling pathway is a viable strategy. TGF-β acts as a tumor suppressor during the first stages of cancer but promotes tumor progression, angiogenesis, immune evasion, and the creation of an immunosuppressive tumor microenvironment in GBM. The deregulation of TGF-β signaling has been shown to interact with essential carcinogenic pathways, including the Wnt/β-catenin, PI3K/AKT, and Notch pathways, therefore aggravating GBM pathogenesis. TGF-β plays a pivotal role in controlling glioma stem cells and influencing the permeability of the blood-brain barrier, making it an attractive target for therapeutic intervention. Novel treatment approaches, including small-molecule inhibitors and monoclonal antibodies, as well as the use of phytochemicals such as flavonoids, quercetin, and other phytochemicals targeting specific elements of the TGF-β signaling pathway, have shown encouraging results in preclinical investigations and early-stage clinical trials. These novel strategies may enhance clinical outcomes and mitigate treatment limitations in GBM therapy by leveraging this system's combined tumor-suppressive and immune-regulatory properties.