Glioblastoma (GBM) is an aggressive primary brain tumor with high lethality. The typical treatment regimen includes post-surgical radiotherapy and temozolomide (TMZ) chemotherapy, which helps extend survival. Nevertheless, TMZ resistance occurs in approximately 50% of patients. This resistance is primarily associated with the expression of O6-methylguanine-DNA methyltransferase (MGMT), which repairs O6-methylguanine lesions generated by TMZ and is thought to be the major mechanism of drug resistance. Additionally, the mismatch repair and base excision repair pathways play crucial roles in TMZ resistance. Emerging studies also point to drug transport mechanisms, glioma stem cells, and the heterogeneous tumor microenvironment as additional influences on TMZ resistance in gliomas. A better understanding of these mechanisms is vital for developing new treatments to improve TMZ effectiveness, such as DNA repair inhibitors, inhibitors of multidrug transporting proteins, TMZ analogs, and combination therapies targeting multiple pathways. This article discusses the main resistance mechanisms and potential strategies to counteract resistance in GBM patients, aiming to broaden the understanding of these mechanisms for future research and to explore the therapeutic effects of traditional Chinese medicines and their active components in overcoming TMZ resistance.