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Radiotherapy is a standard-of-care treatment approach for glioblastoma (GBM) patients, but therapeutic resistance to radiotherapy remains a major challenge. Here we demonstrate that diallyl trisulfide (DATS) directly conjugates with cysteine (C) 32 and C35 (C32/35) residues of thioredoxin 1 (Trx1) through Michael addition reactions. Due to localizing in activity center of Trx1, the conjugation between DATS and C32/35 results in inhibition of Trx1 activity, therefore disturbing thioredoxin system and leading to accumulated levels of reactive oxygen species (ROS). High levels of Trx1 expression are correlated with poor prognosis of glioma patients. Notably, we reveal that DATS synergistically enhances irradiation (IR)-induced ROS accumulation, apoptosis, DNA damage, as well as inhibition of tumor growth of GBM cells. These findings highlight the potential benefits of DATS in sensitizing radiotherapy of GBM patients. [Display omitted] • Thioredoxin 1 (Trx1) was identified as the direct target of Diallyl trisulfide (DATS). • DATS conjugates with C32/35 residues of Trx1 through Michael addition reactions. • The conjugation of DATS with Trx1 inhibited Trx1 activity and disturbed redox balance. • DATS synergistically enhanced the radiotherapy effects of GBM cells. [ABSTRACT FROM AUTHOR]