Neonicotinoid pesticides have been extensively used as plant protectants against weeds and insects. However, their unregulated usage has led to ecological pollution, causing severe impacts on non-target organisms, including fish and humans, who may be exposed to these chemicals through the consumption of contaminated fish meat. This research aimed to investigate the genotoxic and hepatotoxic influences of imidacloprid (IMI, a neonicotinoid pesticide) on juveniles Oreochromis niloticus, and assess the appropriate and affordable price treatment of grape seed extract “GRSE" (anthocyanidin) to minimize the IMI impacts. Exactly 120 fish, weighing 8.85± 0.09g, were distributed into four groups equally; group 1 was the control (fed 0% GRSE), group 2 nourished on 4% GRSE, and both groups were reared in IMI-free water. Group 3 received a 0% GRSE diet and was reared in 2.5 IMI mg/L in water, while the fourth was given a 4% GRSE diet and exposed to 2.5 IMI mg/L in water. After 30 days, blood was collected and analyzed for liver transaminases, lipid profile, leptin hormone and tumor necrosis factor-alpha (TNF-α). Liver tissue samples were assessed for total oxidant capacity (TOC), total antioxidant capacity (TAC) and DNA damage. Gills and livers were sectioned for histopathology; also, the liver was subjected to histochemical and caspase 3 immunohistochemical evaluations. IMI caused hepatotoxicity via enhancement of DNA damage and impairment of liver enzyme, lipid profile, and leptin hormone levels, as well as increased TNF-α and hepatic TOC levels. Additionally, IMI caused histopathological, histochemical and immunohistochemical alterations. These detrimental signs were fully or partially reversed by the administration of a diet enriched with 4% GRSE due to its strong antioxidant and immuno-stimulatory properties, counteracting the negative effects of IMI toxicity in O. niloticus.