AbstractSanggenon C (SC), a herbal flavonoid extracted from Cortex Mori, has been mentioned to possess more than one treasured organic properties. However, the molecular mechanism of its anti‐tumor impact in glioblastoma (GBM) remains unclear. In this study, we reported that SC displayed a GBM‐suppressing impact in vitro and in vivo with no apparent organ toxicity. SC dramatically suppressed cell proliferation‐induced cell apoptosis in GBM cells. Mechanistically, we unveiled that SC modulated the protein expression of death associated protain kinase 1 (DAPK1) by controlling the ubiquitination and degradation of DAPK1. Quantitative proteomic and Western blot analyses showed that SC improved DAPK1 protein degradation via decreasing the expression of E3 ubiquitin ligase Mindbomb 1 (MIB1). More importantly, the effects of SC on cell proliferation and apoptosis of GBM cells have been in part reversed through DAPK1 downregulation or MIB1 overexpression, respectively. These results indicated that SC might suppress cell proliferation and induce cell apoptosis by decreasing MIB1‐mediated DAPK1 degradation. Furthermore, we found that SC acted synergistically with temozolomide (TMZ), an anti‐cancer drug used in GBM, resulting in elevated chemotherapeutic sensitivity of GBM to TMZ. Collectively, our data suggest that SC might be a promising anti‐cancer agent for GBM therapy.