Aeromonas hydrophila, a common cause of disease outbreaks in various fish species, was isolated, biochemically and molecularly identified, and subjected to antimicrobial sensitivity tests. The isolates exhibited multiple resistances toward various antibiotics, so searching for an eco-friendly substitute is essential. Fish feed additives are used to combat potential diseases or stressors. Chitosan and its Nano scale materials, which are anticipated to have stronger immune stimulatory effects than conventional materials, are among these feed additives. Two experiments were performed to compare and assess the therapeutic and adverse impacts of chitosan (Ch) and chitosan-nanoparticles (ChNPs) and assess the efficacy of various treatments against A. hydrophila infection in Oreochromis niloticus. First experiment, O. niloticus (n=180; 26±2 g) were distributed into 3 groups each in triplicate (n=60 fish/group); CTR: negative control; Ch: chitosan (10 g/kg diet); and ChNPs: chitosan nanoparticles (100 mg/kg diet) for 4 weeks. No mortalities or significant negative impacts were noted in any groups. The dietary inclusion of Ch and ChNPs positively impacted fish growth performance, feed intake, hematological parameters, immune response, and antioxidant capacity. It significantly reduced the total aerobic bacterial count in fish flesh, demonstrating the immunostimulant and antibacterial effects of chitosan. Second experiment, each group from the 1^firstexperiment was divided into 2 subgroups of 20 fish each (n=6 groups; 20 fish/group). CTR group subdivided into G1: infected control and G2: infected and treated with levofloxacin (LEV), Ch group subdivided into G3: infected-Ch and G4: infected-Ch+LEV, and ChNPs group subdivided into G5: infected- ChNPs; and G6: infected-ChNPs+LEV for 10 days. The hematological parameters of all the treated groups were closer to the CTR values in the 1^st experiment than in the infected CTR group. Liver enzymes and kidney markers were lower in all treated fish. Immune responses were significantly greater (P≤0.05) in the Ch/ ChNP groups before and after challenge. The mortality rate decreased in the G6 group, followed by the G5 and G4 groups after infection. In conclusion, feeding O. niloticus a 10 g Ch or 100 mg ChNPs/kg diet improved growth performance and enhanced antioxidant capacity.