Recently, there has been a controversy about the hazards of toxic substances released to the aquatic biota. Therefore, the current context is the first attempt to assess the ability of a beneficial medicinal plant, Hyphaene thebaica fruit (HTF) to mitigate various toxic impacts in Clarias gariepinus induced by imidacloprid (IMI) including immune depression, protein impairment, oxidative stress, hepato-renal dysfunction, histopathological, and immune-histochemical alterations. The molecular responses of IMI-induced toxicity at the molecular level and to recognize critical genes altered in response to toxicity are documented. Additionally, we investigated the fish resistance post-challenging with a pathogenic zoonotic bacterium, Aeromonas sobria. Fish (N = 240) were randomly allotted into four random groups in triplicate. The first (control) and second (HTF) groups were fed on basal diets that were enriched with 0.0 and 15 g kg􀀀 1 of HTF without IMI exposure. The third and fourth groups were fed on the same diets and exposed to 1/5 of the 96-h of LC50 of IMI (2.03 μg L􀀀 1) for 60 days. The findings clarified that the IMI exposure significantly augmented (p < 0.05) serum alanine (ALT), aspartate amino-transferases (AST), urea, and creatinine besides malondialdehyde (MDA) levels. While the activities of the protein profile (total protein, albumin, and globulin), immune parameters (lysozyme and immunoglobulin M), and hepatic antioxidant enzymes (superoxide dismutase and glutathione peroxidase) revealed marked depressions in comparison to the control. Histological and immune-histochemical alterations in liver and kidney tissues including vacuolation, severe necrosis, and degeneration, besides weak B-cell lymphoma 2 (BCL-2), potent caspase-3, and down-regulation of genes (IL-1β, IL-8, TNF-α, TGF-β, TLR-5, LYSG, LYSC, NF-κβ, CC, and MYE) were noticed in the IMI-exposed group compared to the control. After 60 days of experimental trial, C. gariepinus challenged by A. sobria exhibited sluggish movement, fin rot accompanied with hemorrhages in different body parts, and severe skin ulcerations with the highest cumulative mortality (80%). Surprisingly, HTF-dietary inclusion enhanced these variables by almost renovating to control values by maintaining histological architecture of the hepatic and renal tissues. Additionally, it increased the fish resistance against A. sobria indicated by reduced mortalities (40%) and enhanced clinical picture. The outputs of the recent study recommend the HTF-dietary supplement to protect against the IMI toxicity in C. gariepinus. And provide insights into the future application of the HTF as an anti-toxic, immune-stimulant, antioxidant, and antibacterial, for improving fish health and sustaining aquaculture. To avoid the deleterious toxic impacts of IMI, this pesticide must be applied carefully, especially near water bodies.