Deltamethrin (DM) is one of the most toxic but widely used pyrethroid insecticides. Even though a non-target animal, fish are at high risk as they are deficient in the enzyme system that hydrolyses pyrethroids. Enhancing the immune system is a potential method in preventing fish diseases. The present investigation aims to study the modulations in the immune response-related parameters in Oreochromis niloticus that were exposed to DM, by dietary supplementation of aqueous root extract of Asparagus racemosus (ARE). The experiment compared fish in control, DM (1 μg/L) exposed (added to water), ARE (10 g, 20 g, and 30 g ARE/kg of feed) supplemented, and DM-ARE cotreated groups. After 21 days of experimental period, serological, histopathological, and immune response related-gene and protein analysis were carried out. The DM-ARE cotreated group showed significant increase in weight gain, specific growth rate, and decreased feed conversion ratio compared to the DM exposed group. The ARE cotreatment could significantly revert the alteration induced by DM in lysozyme, respiratory burst, myeloperoxidase, C-reactive protein, glucose, cortisol, total protein, albumin, and triglyceride levels. The liver histopathology showed membrane breakage, severe necrosis, infiltration of inflammatory cells, melano-macrophages, and nuclear atrophy, and the kidney showed tubular necrosis, hematopoietic necrosis, Bowman's capsule edema, and glomerulus degeneration in DM exposed group. In ARE cotreated group, the liver showed regenerative cellular changes and only mild to moderate cellular damages, and the kidney tubules and glomerulus had intact structure. ARE discernibly regulated the expression of immune-related genes and proteins (IgM, TNFα, IFN-γ, IL-1β, and IL-8) in fish. The DM-ARE cotreated groups showed reduced cumulative mortality and higher relative percent survival on experimental challenge with Aeromonas hydrophila compared to the DM group. Thus, ARE possess protective potential against DM-induced toxicity, and can be used as a cost-effective technique in aquafarming.