Epigenetic regulation of O6-alkylguanine DNA alkyltransferase (MGMT) is surrogate of intrinsic resistance to temozolomide (TMZ). However, mechanisms associated with adaptive resistance evolution of glioblastoma (GBM) relative to MGMT methylation remain unclear. We hereby report a paradoxical yet translational epigenetic regulation of plasticity towards adaptive resistance in GBM. Based on an adaptive resistance model of GBM cells with differential MGMT methylation profiles, MGMT-hypermethylation enhanced genetic and phenotypic plasticity towards adaptive resistance to TMZ while MGMT hypomethylation limited plasticity. The resulting model-associated adaptive resistance gene signature negatively correlated with GBM patient survival. XAF1, a tumor suppressor protein, paradoxically emerged as a mediator of differential plasticities towards adaptive resistance to TMZ through epigenetic regulation. XAF1 promoted resistance both in-vitro and in-vivo. Furthermore, XAF1 expression negatively correlated with XAF1 promoter methylation status, and negatively correlate with GBM patient survival. Collectively, XAF1 appears to have a pradoxical yet translational role in GBM.