Plant-mediated effects on the susceptibility of insect herbivores to entomoviruses are well recognized, but the mechanisms by which plant secondary metabolites impact susceptibility are poorly understood. With widely targeted metabolomics analyses of three plants (Glycine max, Brassica oleracea, Ipomoea aquatica) that caused significant differences in caterpillar (Spodoptera exigua) viral susceptibility, we found four plant phenolics (genistein, kaempferol, quercitrin, coumarin) that increased susceptibility. Subsequently, we analyzed transcriptomes of caterpillars treated with nucleopolyhedrovirus (NPV) alone or with one the four plant phenolics to examine differences in metabolic pathways. We found that phenolic treatments caused significant differences in genes up-or-down regulating cytochrome P450, glutathione S-transferase and consistently caused significant down-regulation of the CXE18 gene regulating antennal esterase in caterpillars. This study found four phytochemicals can be potential candidate NPV synergist and sheds light on the mechanisms driving insect susceptibility to entomoviruses.