Natural plant dietary supplementation in aquafeed could be used as an effective way for increasing the immunocompetency and disease resistance of fish. The current study aimed to investigate the potential effects of dietary Moringa oleifera leaf powder supplementation on the immune response, antioxidant status, and disease resistance against Aeromonas hydrophila in Oreochromis niloticus. A total of 180 fish (of 2.6 ± 0.5 g average weight) were randomly divided into three groups and fed on basal diet (= controls), and 1.5 and 5% (w/w) M. oleifera leaf powder incorporated into diets for 60 days. After the feeding trial, fish were challenged with A. hydrophila and continued on the same feeding regime during the next 2 weeks. Oral administration of O. niloticus fry with M. oleifera leaf powder led to significantly enhanced immune responses, i.e., respiratory burst, phagocytic and lysozyme activities, IgM level, and antioxidant enzyme activities, namely superoxide dismutase, catalase, and glutathion peroxidase levels in the liver, kidneys, and spleen. Conversely, the malondialdehyde level decreased significantly in the liver and kidneys. There was a significant increase in white blood cell count and non-significant change in red blood cell count and hemoglobin levels. Following challenge with A. hydrophila, all the fish in the experimental groups survived compared to only 20% of the controls; the relative percent survival was 100%. However, there was not any significant effect on growth as a result of feeding with the experimental diets. These results suggested that M. oleifera leaf powder-supplemented diets could enhance the immune response of O. niloticus fry and prevent disease caused by A. hydrophila.