A chemical scaffold-hopping approach from known 3-hydroxyl-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors identified (E/Z)-2-arylstilbenes as novel insecticidal hits against two lepidopteran species, Spodoptera exigua and Trichoplusia ni. A structure-activity relationship (SAR) study of the aryl substituents and the E/Z conformations was carried out in an effort to improve insecticidal potency. A series of (E/Z)-2-arylstilbenes was prepared and separated to evaluate their insecticidal potency against lepidopterous species in diet-feeding assays. The results showed that the (Z)-2-arylstilbenes were more active than their corresponding (E)-isomers, and a stereoselective synthesis was utilized to expand the SAR of the (Z)-2-arylstilbenes. (Z)-4'-Fluoro-3'-methyl-2-(2,4-difluorostyryl)-4-fluoro-5-methoxy-1,1'-biphenyl was the most potent analog in this study with strong activity against S. exigua, T. ni, Helicoverpa zea, Plutella xylostella and Pseudoplusia includens. The (Z)-2-arylstilbenes were found to have strong insecticidal potency against five lepidopteran species. Ultimately, synthetic efforts could not improve insecticidal potency to commercial levels, and a lack of UV stability led to efforts being discontinued. © 2019 Society of Chemical Industry. © 2019 Society of Chemical Industry.