Glioblastoma (GBM) is an aggressive malignancy with a high rate of tumor recurrence after treatment with conventional therapies. Parthenolide (PTL), a sesquiterpene lactone extracted from the herb Tanacetum parthenium or feverfew, possesses anticancer properties against a wide variety of solid tumors. In the present study, a series of PTL derivatives were synthesized and screened. An inhibitor, dimethylaminoparthenolide (DMAPT)‑D6, a derivative of the PTL prodrug DMAPT in which the hydrogen of the dimethylamino group is substituted for the isotope deuterium, induced significant cytotoxicity in GBM cells in vitro and induced cell cycle arrest at the S‑phase in a dose‑dependent manner. Furthermore, mechanistic investigation indicated that through increasing the levels of intracellular accumulation of reactive oxygen species (ROS), DMAPT‑D6 triggered DNA damage and finally death receptor‑mediated extrinsic apoptosis in GBM cells, suggesting that DNA damage induced by DMAPT‑D6 initiated caspase‑dependent apoptosis to remove damaged GBM cells. Taken together, these data suggested that ROS accumulation following treatment with DMAPT‑D6 results in DNA damage, and thus, death‑receptor‑mediated apoptosis, highlighting the potential of DMAPT‑D6 as a novel therapeutic agent for the treatment of GBM.