Three diverse insects, a polyphagous “leaf chewer” (Atractomorpha lata), a polyphagous “sap feeder” (Myzus persicae), and a “restrictive feeder” (Plutella xylostella) responded differently when fed with eight cultivars of sesame either as whole leaf or via artificial diet. There was limited or no correlation in induction between detoxifying enzyme substrates (esterase, glutathione s-transferase [GST], and mixed function oxidase [MFO] activities) when activity toward various substrates α-naphthyl acetate, 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene, and p-nitroanisole (pNA), were compared although they were generally elevated in the tissues from insects on sesame than a reference fed with radish seedlings. In A. lata, esterase activity for the cultivar 11Pusan and 45Laos were three-fold higher compared to the reference, while other cultivars, 24Nanbu-twasaki and 56S-radiatum were—two- to three-fold lower than the reference. In M. persicae, the esterase activity was as much as five-fold higher than the reference in one test cultivar. GST activities of the sesame cultivars were generally higher (≈two-fold) than the reference in all insects and at variable ratios among the cultivars. The MFO activity toward pNA in grasshoppers feeding on these sesame cultivars was either highly expressed or nonexistent. These results indicate that although the cultivars belong to the same species, they might have undergone changes in secondary phytochemicals in response to varying biogeographical distribution. Each insect species is suspected to target a specific plant chemical burden that it tries to overcome in each cultivar through enzyme activation.