This study was performed to investigate the effect of the dietary supplementation of chitosan-vitamin C nanocomposite (CVCN) at four different concentrations (0, 200, 300, 400 mgkg􀀀 1 diet) in Nile tilapia (Oreochromis niloticus) fingerlings, for ten weeks feeding period, on the growth performance, antioxidant activity, immune status, histopathology of some organs, and disease resistance against Aeromonas sobria (A. sobria). A total of 180 fingerlings (average initial weight = 14.74 ± 0.016 g) were randomly allotted to four groups. Different concentrations of CVCN significantly increased the final body weight, body weight gain, feed conversion ratio, the protein efficiency ratio, specific growth rate%, and daily weight gain in a dose-dependent manner (P < 0.05). A significant increase (P = 0.03) in the serum vitamin C level was observed at the highest concentration (400 mgkg􀀀 1) of CVCN. A significant increase (P = 0.00) in the serum growth hormone level was observed at all concentrations of CVCN in a dose-dependent manner. There was a significant increase (P < 0.05) in the serum and hepatic levels of superoxide dismutase and glutathione, and decrease in serum Malondialdehyde, by increasing the level of vitamin supplementation compared to the zero level. Likewise, there was a significant increase (P < 0.05) in the serum levels of lysozyme, nitric oxide, relative percent survivability, and phagocytic percentage with an increase in the vitamin level, and the best results were observed at 400 mgkg􀀀 1CVCN. Histologically, CVCN increased the villus height, goblet cell count, and intra-epithelium lymphocytes of the proximal part of the intestine. Therefore, the dietary supplementation by CVCN improved the fish growth performance, and CVCN at 400 mgkg􀀀 1 the best dietary level of for O. niloticus fingerlings that exhibited improve the antioxidant status, intestinal histology, immune response, and disease resistance.