The small-molecule alkylating agent temozolomide (TMZ) is commonly used as a frontline therapy for glioblastoma multiforme (GBM). However, there are certain factors, such as the presence of O6-methylguanine-DNA methyltransferase (MGMT) and activated DNA repair pathways, that can lead to resistance to TMZ, thereby limiting its effectiveness. This paper aims to comprehensively review the detailed molecular mechanisms behind TMZ resistance, discuss innovative therapeutic strategies to overcome resistance, and explore potential drugs that may enhance the efficacy of TMZ. Ultimately, our goal is to provide valuable insights into clinical approaches for mitigating TMZ resistance in GBM patients.