This review discusses approaches to enhance the activity of temozolomide (TMZ) against glioblastoma (GBM) to overcome resistance. GBM is a highly aggressive and treatment-resistant tumor with a poor prognosis. The standard treatment includes surgical resection, radiation, and TMZ chemotherapy, but resistance often develops, leading to tumor recurrence and severe side effects. TMZ resistance is associated with mechanisms such as hyperactivation of DNA repair pathways, increased expression of drug transporters, and mutations in signaling pathways. Strategies to overcome resistance include chemosensitizers, drug delivery systems, and targeting specific pathways like MGMT, DNA repair, and Glioma Stem Cells (GSCs). Approaches such as PARP inhibitors, EGFR inhibitors, and Wnt/β-catenin pathway inhibitors have shown promise in enhancing TMZ activity. Additionally, formulation strategies aim to improve TMZ's brain penetration and systemic exposure by modifying its pharmacokinetics. These approaches highlight the need for innovative therapies to improve outcomes for GBM patients.This review discusses approaches to enhance the activity of temozolomide (TMZ) against glioblastoma (GBM) to overcome resistance. GBM is a highly aggressive and treatment-resistant tumor with a poor prognosis. The standard treatment includes surgical resection, radiation, and TMZ chemotherapy, but resistance often develops, leading to tumor recurrence and severe side effects. TMZ resistance is associated with mechanisms such as hyperactivation of DNA repair pathways, increased expression of drug transporters, and mutations in signaling pathways. Strategies to overcome resistance include chemosensitizers, drug delivery systems, and targeting specific pathways like MGMT, DNA repair, and Glioma Stem Cells (GSCs). Approaches such as PARP inhibitors, EGFR inhibitors, and Wnt/β-catenin pathway inhibitors have shown promise in enhancing TMZ activity. Additionally, formulation strategies aim to improve TMZ's brain penetration and systemic exposure by modifying its pharmacokinetics. These approaches highlight the need for innovative therapies to improve outcomes for GBM patients.