Objective: Parthenolide?(PTL) induces anti?tumor effects via the nuclear factor kappa B?(NF?κB) signaling pathway. MCL3, a PTL derivative, is a sesquiterpene lactone synthesized by the rearrangement and subsequent oxidation of PTL. The aim of this study was to elucidate the antitumor activity and mechanism of action of MCL3 in glioblastoma?(GBM). Materials and Methods: The effects of MCL3 on G422 cell proliferation, apoptosis, invasion, and angiogenesis in? vitro were measured using the 3?(4,5?dimethylthiazol?2?yl)?2,5?diphenyltetrazolium bromide assay, flow cytometry, the cell invasion, and tube formation assays. The subcutaneously transplanted G422 xenograft model was used to detect the effect of MCL3 on tumor growth in? vivo. Pathological changes were analyzed by immunohistochemical staining. The effects of MCL3 on NF?κB and Stat3 transcriptional activities were examined using a dual?luciferase reporter assay. Protein levels related to the NF?κB/interleukin?(IL)?6/Stat3 signaling pathway were determined using western blot analysis. Results: MCL3 inhibited GBM cell proliferation, invasion, and angiogenesis in a concentration?dependent manner. Moreover, MCL3 decreased the transcriptional activities of NF?κB and Stat3. MCL3?suppressed tumor growth in the subcutaneously transplanted G422 xenograft model, while the inhibition rate was 79％ in tumor weight at 40.0 mg/kg. MCL3 blocked the NF?κB/IL?6/Stat3 signaling pathway in G422 cells and tumor tissues, resulting in the downregulation of Stat3 target genes related to apoptosis, invasion, etc., Conclusion: The results show that MCL3 might inhibit G422 GBM growth partly due to the inhibition of the NF?κB/IL?6/Stat3 signaling pathway.