Ctenopharyngodon idellus is an important commercial fish species in China and many other countries to meet human food habits. However, there is no definitive data to indicate the multi-infection of pathogenic Aeromonas hydrophila strains in cultured C. idellus. In this study, four strong virulent strains with five virulence genes were simultaneously isolated from the cultured C. idellus suffering from septicemia, and identified as different A. hydrophila isolates using the ATB 32GN system, phylogenetic analysis, enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR). They were susceptible to chloramphenicol, tobramycin, kanamycin, norfloxacin, spectinomycin, furantoin, azithromycin, and resistant to carbenicillin, penbritin, clindamycin. In addition, to further control the multi-infection of A. hydrophila, norfloxacin, the well-known fishery drug widespread used in aquaculture, was employed to treat this disease. Its minimum inhibitory concentrations (MICs) were 2 similar to 4 mg/L and good protection effects were also exhibited on the naturally infected fish at a final concentration of 1 and 2 g/Kg in the feed (cal. 20 and 40 mg/Kg of fish). As an important pathogen of a zoonotic and foodborne disease, the multi-infection of A. hydrophila strains may be an emerging threat in grass carp farming and food safety, and more importance should be attached to their multi-infection in fish farming.