Further mechanistic investigation revealed that curcumol blocked the active site Phe178 of NQO2, suppressed NQO2 activity to cause ROS generation, initiating endoplasmic reticulum (ER) stress‐C/EBP homologous protein (CHOP)‐death receptor (DR5) signaling for sensitizing NSCLC to TRAIL‐induced apoptosis, highlighting a critical role of NQO2 in TRAIL resistance and a synergistic lethal effect of curcumol/TRAIL in cancer therapy. This evidence concerns the gene DDIT3 and cancer.