Glioblastoma (GBM) is a highly aggressive and immunologically challenging tumor, often referred to as an "immune-cold tumor." Its treatment is hampered by a variety of factors, including a highly immunosuppressive tumor microenvironment (TME), the presence of the blood-brain barrier (BBB), and tumor heterogeneity. These challenges limit the efficacy of conventional therapies. Immune checkpoint inhibitors (ICBs), while effective in many cancers, show limited success in GBM, with response rates ranging from 10% to 30%. To overcome these limitations, novel immunotherapeutic approaches, such as bispecific antibodies (BsAbs) and bispecific T-cell engagers (BiTEs), have emerged as promising alternatives. BsAbs, which can simultaneously bind tumor cells and T cells to enhance immune responses, have shown remarkable success in hematologic cancers like acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). In GBM, targeting overexpressed proteins such as EGFRvIII, HER2, L1CAM,and B7-H3 with BsAbs has demonstrated the potential to improve immune responses and induce T-cell infiltration, leading to enhanced tumor killing. Among these, EGFRvIII-targeted BsAbs have shown significant anti-tumor activity in preclinical models, with prolonged survival observed in glioma-bearing mice. These findings suggest a promising clinical application for EGFRvIII-targeted BsAbs in GBM therapy. In addition to BsAbs, BiTEs, which are designed to activate T cells and induce tumor cell lysis, have been tested in GBM models. BiTE therapies targeting EGFRvIII, such as AMG596 and hEGFRvIII-CD3, are currently undergoing clinical trials. Preclinical studies have shown that BiTEs can trigger a strong and sustained anti-tumor immune response, leading to significant tumor regression in mouse models. Furthermore, the combination of BiTEs with immune checkpoint inhibitors or radiotherapy holds potential to further enhance therapeutic efficacy. Despite the promising results, the application of BsAbs and BiTEs in GBM faces several challenges. These include overcoming the BBB to ensure effective drug delivery, minimizing immune-related side effects such as cytokine release syndrome (CRS), and optimizing antibody affinity and specificity to avoid damage to normal tissues. Additionally, strategies that combine BsAbs or BiTEs with other therapeutic modalities, such as immune checkpoint inhibitors or targeted radiation, could improve treatment outcomes. Emerging self-assembling and disassembling (SADA) platform technologies offer a new approach to enhance treatment specificity and reduce toxicity. In conclusion, while BsAbs and BiTEs represent promising therapeutic strategies for GBM, further research and clinical trials are needed to address the challenges associated with their application. With continued innovation and optimization, these therapies hold the potential to improve patient prognosis and provide new treatment options for this devastating disease.