In our study, we used in silico screening, molecular pharmacological technologies and iTRAQ-based proteomics analysis to screen and discover a novel small-molecule activator of SIRT1 (Comp 5) with brilliant anticancer activity of glioblastoma in vitro and in vivo without obvious toxicity, suggesting that application of SIRT1 activators was a promising strategy in cancer. Here, SIRT1 is linked to glioblastoma.