Aim: The current work was performed to scrutinize the impacts of A. hydrophila infection on the occurrence of mortalities, altering the clinical picture of fish, antioxidants-associated gene expression, and histopathological architecture of the Cyprinus carpio and Oreochromis niloticus. Methods: Juvenile fishes including C. carpio, n = 60, and O. niloticus, n = 60 were haphazardly alienated into the control group (uninfected) and infected group with 100 μl of A. hydrophila. Mortalities and clinical signs were recorded during the experiment. Samples of liver, kidney, and spleen were collected post-infection for 7 days to monitor the expression of superoxide dismutase, glutathione peroxidase, and catalase genes, plus the assessment of histopathology. Results: The rate of mortalities was higher in C. carpio compared to O. niloticus. Additionally, infected O. niloticus revealed red eyes and erythema, while C. carpio showed exophthalmia and severe skin ulceration with exposure to viscera. The gene expression indicators showed that A. hydrophila significantly declined on the 1st day and the 7th day after infection, but significantly increased (p < 0.05) on the 3rd day compared to their respective control groups for C. carpio. Meanwhile, O. niloticus significantly regulated gene expression (p < 0.05) in the control groups. The histological picture indicated that the liver is the most affected organ. Moreover, C. carpio exhibited more disruption in histological architecture related to O. niloticus. Conclusion: Overall, A. hydrophila is extremely virulent and results in higher mortalities, profound clinical manifestations, down-regulation in the gene expression, and histopathological alterations in the hepato-renal and splenic tissues of C. carpio and O. niloticus. Cyprinus carpio was more adversely affected by the infection compared to O. niloticus. However, O. niloticus revealed higher gene expression, particularly in the spleen, and the genes were more expressed in comparison to C. carpio.