Escherichia coli (E. coli) are typically present as commensal bacteria in the gastro-intestinal tract of most animals including poultry species, but some avian pathogenic E. coli (APEC) strains can cause localized and even systematic infections in domestic poultry. Emergence and re-emergence of antimicrobial resistant isolates (AMR) constrain antibiotics usage in poultry production, and development of an effective vaccination program remains one of the primary options in E. coli disease prevention and control for domestic poultry. Thus, understanding genetic and pathogenic diversity of the enzootic E. coli isolates, particularly APEC, in poultry farms is the key to designing an optimal vaccine candidate and to developing an effective vaccination program. This study explored the genomic and pathogenic diversity among E. coli isolates in southern United States poultry. A total of nine isolates were recovered from sick broilers from Mississippi, and one from Georgia, with epidemiological variations among clinical signs, type of housing, and bird age. The genomes of these isolates were sequenced by using both Illumina short-reads and Oxford Nanopore long-reads, and our comparative analyses suggested data from both platforms were highly consistent. The 16 s rRNA based phylogenetic analyses showed that the 10 bacteria strains are genetically closer to each other than those in the public database. However, whole genome analyses showed that these 10 isolates encoded a diverse set of reported virulence and AMR genes, belonging to at least nine O:H serotypes, and are genetically clustered with at least five different groups of E. coli isolates reported by other states in the United States. Despite the small sample size, this study suggested that there was a large extent of genomic and serological diversity among E. coli isolates in southern United States poultry. A large-scale comprehensive study is needed to understand the overall genomic diversity and the associated virulence, and such a study will be important to develop a broadly protective E. coli vaccine.