Aeromonas veronii, a threatening fish pathogen, is implicated in food-borne infections in humans, contributing to substantial economic losses in the aquaculture sector. To examine the occurrence, resistance profiles, 16SrRNA sequence analysis, virulence-determinant and resistance genes, and pathogenicity of A. veronii isolated from Nile tilapia (Oreochromis niloticus), almost 150 fish weighing 75 ± 10 g (apparently healthy; n = 50 and moribund fish; n = 100) were collected from commercial farms in Ismailia Governorate, Egypt. Subsequently, the clinical, post-mortem, and bacteriological examinations were carried out. The overall prevalence of A. veronii in the collected O. niloticus was 18.6% (28/150), where the pathogen was only detected in the moribund one. Phylogenetic analysis revealed that the tested isolate exhibited significant genetic identity with other strains from diverse locations and origins in China and Egypt. PCR showed that aerA (95.4%) was the most predominant virulence gene associated with A. veronii isolates retrieved from O. niloticus, followed by hly (80.3%), ast and ser (69.7% for each), and alt (50.1%). Moreover, 40.9% of the obtained isolates were extensively drug-resistant (XDR) to seven classes and inherited blaTEM, tetA, blaCTX-M, and sul1 genes. Besides, 6.1% of the recovered isolates were carbapenem-resistant and XDR to seven classes harboring blaTEM, blaNDM, blaCTX-M, sul1, and tetA genes. The cumulative mortality rate was 86.7% in the fish group injected with a virulent A. veronii strain at a concentration of 3 × 108 CFU/mL. Concisely, this study underscored the existence of XDR A. veronii in O. niloticus specifying a public health hazard. XDR A. veronii isolated from O. niloticus commonly inherited aerA, ast, ser, and alt virulence-determinant genes and blaTEM, sul1, blaCTX-M, and tetA resistance genes.