Here, we synthesized a novel series of indolyl-chalcone derivatives and identified a new Nrf-2 activator named indolyl-chalcone derivative 3d, which dramatically inhibited tumor growth in vitro and in vivo by inducing A549 lung cancer cell apoptosis and activating Nrf-2/HO-1 pathway. This evidence concerns the gene NFE2L2 and neoplasm.