Sugarcane aphid (Melanaphis sacchari) is a phloem-feeding insect that severely affects the growth and productivity of sorghum and other related crops. While a growing body of knowledge is accumulating regarding plant, and insect interactions, the role of reactive oxygen species (ROS) against aphid infestation in sorghum has not been established yet. Here, the involvement of H2O2 and ROS detoxification enzymes in host plant resistance to sugarcane aphid in sorghum was demonstrated. The H2O2 accumulation and expression patterns of selected ROS scavenging enzymes including ascorbate peroxidase (APX), glutathione S transferase (GST), superoxide dismutase (SOD), and catalase (CAT) in response to sugarcane aphid infestation at 3, 6, 9, and 12 days post infestation (dpi) in resistant (Tx2783) and susceptible (Tx7000) sorghum genotypes were assessed, respectively. A significant increase in H2O2 accumulation was observed in resistant genotypes at all time points studied as compared to susceptible plants. Furthermore, gene expression analysis revealed that in responding to attack by sugarcane aphid, antioxidant genes were induced in both genotypes, but much stronger in the resistant line. Furthermore, aphid survival and fecundity were significantly inhibited in resistant plants compared to susceptible plants. Taken together, our results suggest that the elevated accumulation of H2O2 and the strong upregulation of the antioxidant genes in sorghum may have contributed to host plant resistance in Tx2783 against sugarcane aphid but the weak expression of those antioxidant genes in Tx7000 resulted in the failure of attempting defense against sugarcane aphid. This report also provides the experimental evidence for the role of ROS involvement in the early defensive response to an attack by sugarcane aphid in sorghum.