Plants are equipped with a wide range of defensive mechanisms such as morphophysiological, biochemical, molecular, and hormonal signaling for protecting against insect-pest infestation. The infestation of a devastating pest shoot fly [Atherigona soccata (Rodani)] at seedling stage causes huge loss of sorghum crop productivity. In morphophysiological screening ICSV700, ICSV705, and IS18551 have been categorized as resistant, PSC-4 moderately resistant, SL-44 and SWARNA as susceptible. The present study focused on the role of defensive gene expression and its products viz: superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione reductase (GR), polyphenol oxidase (PPO), phenyl alanine ammonia lyase (PAL), responsive enzymes, and metabolites restoring redox status in sorghum plants against shoot fly infestation. In both leaf and stem tissue of sorghum genotypes, shoot fly infestation induced SOD, APX, DHAR, GR, PAL, and PPO activities while CAT activity was significantly declined at 15 and 21 days after emergence (DAE). IS18551 with resistant behavior showed upregulation of SOD, GR, APX, and DHAR along with accumulation of ascorbate, glutathione enhancing redox status of the plant during shoot fly infestation at later stage of infestation. While SWARNA with susceptible response exhibited enhanced activity of phenylpropanoid pathway enzymes PAL and PPO which in turn increased the levels of secondary metabolites like o-dihydroxyphenol and other phenols deterring the insect to attack the plant. The qRT-PCR data predicted that stress-responsive genes were initially unregulated in SWARNA; however, at 21 DAE, multifold higher expression of SOD, CAT, APX, and PPO (24.8-, 37.2-, 21.7-, and 17.9-fold respectively) in 1S18551 indicates the resistance behavior of this genotype against insect infestation owing to sustainable development capability.