In order to determine the pathogen and pathogenic characteristics of diseased blunt snout bream (Megalobrama amblycephala) in a farm in Hubei Province, as well as to analyze the virulence and drug-resistance characteristics of the pathogen through the whole genome, a strain of pathogenic bacteria (LHW39) was isolated from the liver lesions of the diseased blunt snout bream. Based on 16S rRNA identification and physiological and biochemical characteristics, LHW39 was identified as Aeromonas hydrophila. Multi-sequence typing showed that LHW39 belongs to the ST251 clonal group, the epidemic strain group causing the outbreak of motile Aeromonas septicemia (MAS) in China and the USA. Artificial infection tests confirmed its pathogenicity to blunt snout bream. The median lethal concentration of LHW39 to zebrafish (Danio rerio) was 1.55×105 CFU/fish, suggesting that LHW39 is highly virulent. Drug susceptibility tests demonstrated that LHW39 was resistant to cephalothin. Whole genome sequencing results showed that strain LHW39 contained a chromosome of 5,099,855 bp with an average G+C content of 60.80% and 4,572 coding sequences (CDS). Its complete genome has been deposited at GenBank under the accession number CP050012. Genomic comparative analysis suggested that the virulence genes of LHW39 are plentiful and highly similar to those of other ST251 strains. LHW39 also contains a type VI secretion system (T6SS). In addition, a heat map suggests that the evolution of the virulence-related genes of strains in the ST251 clonal group might be related to the geographical locations or the infected hosts of the isolates. A complete prophage named phAhLHW39 (30.2 kb) is presented in the LHW39 genome, which is highly conserved among ST251 strains and is unique to ST251. Analysis of drug-resistance genes showed that LHW39 contained resistance genes related to antibiotics such as sulfonamides, quinolones, tetracyclines, cephalosporins, and carbapenems, all of which were highly conserved among ST251 strains. In this study, pathogenic and genome-wide comparative analysis of the pathogenic A. hydrophila strain LHW39 was carried out, which provides references for the prevention and control of fish diseases caused by A. hydrophila.