Temozolomide (TMZ) has been widely used in the treatment of glioblastoma (GBM), although inherent or acquired resistance restricts the application.This study was aimed to evaluate the efficacy of sulforaphane (SFN) to TMZ-induced apoptosis in GBM cells and the potential mechanism.Biochemical assays and subcutaneous tumor establishment were used to characterize the function of SFN in TMZ-induced apoptosis.Our results revealed that β-catenin and miR-21 were concordantly expressed in GBM cell lines, and SFN significantly reduced miR-21 expression through inhibiting the Wnt/β-catenin/TCF4 pathway.Furthermore, down-regulation of miR-21 enhanced the pro-apoptotic efficacy of TMZ in GBM cells.Finally, we observed that SFN strengthened TMZ-mediated apoptosis in a miR-21-dependent manner.In conclusion, SFN effectively enhances TMZ-induced apoptosis by inhibiting miR-21 via Wnt/β-catenin signaling in GBM cells.These findings support the use of SFN for potential therapeutic approach to overcome TMZ resistance in GBM treatment.