By introducing the 9th larval instar of the red palm weevil (RPW), Rhynchophorus ferrugineus, to feed on sugarcane stem dipped in insecticide solutions of chlorpyrifos, methomyl, and spinosad to monitor the biochemical and histological changes in larvae after 24 h exposure. The estimated LC50 values for chlorpyrifos, methomyl and spinosad were 109.73, 589.55 and 112.09 μg a.i/ml, respectively. Exposure of RPW larvae to LC50s of the tested insecticides causes a significant inhibition in Acetylcholinesterase activity associated with increasing total protein in all treatments but alanine aminotransferase and aspartate aminotransferase activities enhanced with methomyl but decreased in spinosad-larvae treated. Chlorpyrifos was only significantly induced oxidative stress (increasing protein carbonyl indicator) followed by increasing antioxidant enzymes (catalase and glutathione peroxidase). While superoxide dismutase and glutathione peroxidase were reduced significantly in methomyl and spinosad treatments. Catalase activity raised significantly with chlorpyrifos followed spinosad. All the treatments of insecticides exhibited lower glutathione-S-transferases activities especially in spinosad than chlorpyrifos treatments. The histological damage in the midgut of larvae treated included vacuolar degeneration, proliferation, and necrosis of epithelial lining with destruction and separation of basement membrane and with desquamation in its lumen. In conclusion, spinosad insecticide was more effect on biochemical and histopathological responses of RPW than both methomyl and chlorpyrifos insecticides.