Resistance to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) of cancer cells is a main obstacle for the chemotherapy. NRH: quinone oxidoreductase 2 (NQO2), known as a chemopreventive target, has emerged as a promising therapeutic target for overcoming TRAIL resistance in non-small cell lung cancer (NSCLC). Here we report the design, synthesis and evaluation of resveratrol analogues as novel selective NQO2 inhibitors, and analogue 20b, with potent NQO2 inhibitory activity (IC