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Antibiotic‐resistant Aeromonas veronii isolates (4) were identified from moribund Oreochromis niloticus by phenotypic and genotypic characterization using 16S rDNA gene sequence analysis. Antibacterial efficacy of silver nanoparticles (AgNPs) was assessed in vitro and in vivo against A. veronii isolates. A minimum inhibitory concentration (MIC) and 48 h lethal concentration 50% (LC50) for AgNPs were estimated to be 3.125 μg/ml and 8.77 mg/L respectively. Four hundred fifty fish were divided into 10 groups in triplicate (15/replica). Two control groups were untreated with AgNPs: The first (G1) was not infected, whereas the second (G2) was experimentally infected with A. veronii. AgNPs were added to aquarium water with fish either noninfected (G3–G6) or infected (G7–G10) with A. veronii. AgNPs concentrations were 100, 250, 500 and 750 μg/L, respectively, for both sets of fish groups. Fish infected with A. veronii but untreated with AgNPs showed septicaemic symptoms, a high mortality rate (71%) and poorer haematological parameters (red blood cells [RBCs], haemoglobin concentration [Hb], hematocrit [HCT%], mean cell volume [MCV] and mean cell haemoglobin [MCH]); impaired nonspecific immune responses (total protein, albumin, globulin and lysozymes); reduced antioxidant capacity (catalase [CAT], peroxidase and superoxide dismutase [SOD]); a significant increase in creatinine, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP); and genotoxic effects in gills. Treatment with AgNPs increased fish survival; improved haematological, immunological and antioxidant activities; and optimized liver and kidney function. The most favourable outcome was seen using an AgNPs concentration of 750 μg/L. Various histopathological changes were found among experimental fish. [ABSTRACT FROM AUTHOR]