Recently, the concept of incorporating natural products into nanocarriers has been intended to promote fish growth and health via modulating their stability and bioavailability. In this concern, the potential role of reformulated quercetin into nanocarriers was examined, for the first time, on Nile tilapia’s performance and immunity, flesh quality and antioxidant indices and disease resistance. Five hundred fish assigned into five experimental groups with formulated diets containing quercetin nanoparticles (QT-NPs) at levels of 0, 100, 200, 300 and 400 mg/kg were challenged with Aeromonas hydrophila (A. hydrophila) after 12 weeks feeding trial. Fish’s final body weight gain and feed efficiency were significantly maximized in groups enriched with 300 and 400 mg/kg of QT-NPs. Significant reduction in total saturated fatty acids and an elevation in polyunsaturated fatty acids’ contents were noticed in fish fed higher QT-NPs doses. The levels of Hydrogen peroxide, reactive oxygen species and malondialdehyde, the markers of meat antioxidant capacity, were reduced by higher inclusion levels of QT-NPs. Accordingly, serum activities and transcriptional levels of GSH-Px, CAT and SOD genes were increased with elevated QT-NPs levels. Immune responses mediated by upregulation of IL-10 and TGF-β and downregulation of IL-1β, IL-8 and TNF-α mRNA levels were found to be positively affected by QT-NPs. Dietary QT-NPs downregulated the expression of ahyI and ahyR quorum sensing genes conferring protection against A. hydrophila challenge. This study concluded that supplementation of quercetin in encapsulated nanoparticles could improve its efficacy making it as a compelling approach to improve fish performance and as a promising drug candidate against A. hydrophila virulence.