Eicosandoids, or icosanoids, are signaling compounds created by the oxidation of 20-carbon fatty acids. They control many complex physiological and immunological functions in vertebrate and invertebrate animals. This study tested the hypothesis that eicosanoids act in insect antioxidant defense. The effects of 3 eicosanoid biosynthesis inhibitors (EBIs) – dexamethasone, esculetin, and phenidone – on the oxidative stress indicator, malondialdehyde (MDA), and the detoxification enzyme, glutathione S-transferase (GST), was examined in the midgut of larvae of the greater wax moth, Galleria mellonella (L.). The larvae were reared on artificial diets supplemented with 0.001, 0.01, 0.1 or 1.0% of the EBIs. Esculetin, which is a lipoxygenase inhibitor, significantly increased MDA content; whereas, GST activity was significantly increased at only the highest concentration tested. Dexamethasone, a phospholipase A₂ inhibitor, significantly increased MDA content and GST activity at concentrations of 0.01, 0.1, and 1.0%. Phenidone, a dual inhibitor of cyclooxygenase and lipoxygenase, increased MDA content, whereas the 0.01 and 0.1% concentrations of phenidone significantly increased GST activity. Our results indicate that antioxidative responses are, at least in part, controlled by a physiological system that includes eicosanoid biosynthesis.