To prevent their ingestion by phytophagous insects, plants produce secondary metabolites as defensive weapons. Conversely, insects need to counter these metabolites to survive. Different species, though they are closely related, can evolve distinct strategies to resist plant-derived factors. However, the mechanism under this high divergence resistance is still unclear at a molecular level. In this study, we focus on how Spodoptera litura (Lepidoptera; Noctuidae) detoxifies phytoecdysteroids, a class of metabolites capable of disrupting the normal development of insects. Firstly, we find that the S. litura show resistance to artificial foods containing a high level of 20-hydroxyecdysone (20E), the major form of phytoecdysteroids, without any adverse effects on growth and development. Furthermore, a comparative transcriptomic analysis between S. litura and another noctuid insect ( Helicoverpa armigera ) was performed. Almost all known ecdysteroid degradation pathways including 3-epimerization, 22-phosphorylation, 22-esterification, and 26-hydroxylation were upregulated in the midgut of 20E treated S. litura larvae, whereas only 22-esterification and 26-hydroxylation were enhanced in H. armigera larvae. In summary, though both species belong to the Noctuidae family, they evolved two different strategies to tolerate a high dosage of ingested 20E.