Temozolomide　(TMZ)　is　currently　the　first-line　chemotherapeutic　agent　for　the　treatment　of　glioblastoma　multiforme　(GBM).　However,　the　inherent　heterogeneity　of　GBM　often　results　in　suboptimal　outcomes,　particularly　due　to　varying　degrees　of　resistance　to　TMZ.　Over　the　past　several　decades,　O　6-methylguanine-DNA　methyltransferase　(MGMT)-mediated　DNA　repair　pathway　has　been　extensively　investigated　as　a　target　to　overcome　TMZ　resistance.　Nonetheless,　the　combination　of　small　molecule　covalent　MGMT　inhibitors　with　TMZ　and　other　chemotherapeutic　agents　has　frequently　led　to　adverse　clinical　effects.　Recently,　additional　mechanisms　contributing　to　TMZ　resistance　have　been　identified,　including　epidermal　growth　factor　receptor　(EGFR)　mutations,　overactivation　of　intracellular　signalling　pathways,　energy　metabolism　reprogramming　or　survival　autophagy,　and　changes　in　tumor　microenvironment　(TME).　These　findings　suggest　that　novel　therapeutic　strategies　targeting　these　mechanisms　hold　promise　for　overcoming　TMZ　resistance　in　GBM　patients.　In　this　review,　we　summarize　the　latest　advancements　in　understanding　the　mechanisms　underlying　intrinsic　and　acquired　TMZ　resistance.　Additionally,　we　compile　various　small-molecule　compounds　with　potential　to　mitigate　chemoresistance　in　GBM.　These　mechanism-based　compounds　may　enhance　the　sensitivity　of　GBM　to　TMZ　and　related　chemotherapeutic　agents,　thereby　improving　overall　survival　rates　in　clinical　practice.