Extensive genomic analyses of Enterococcus cecorum isolates from sepsis outbreaks in broilers suggests a polyphyletic origin likely arising from core genome mutations rather than gene acquisition. This species is normal intestinal flora in avian species with particular isolates associated with osteomyelitis. More recently, the species has been associated with sepsis outbreaks affecting broilers during the first 3 weeks post hatch. Understanding the genetic and management basis of this new phenotype is critical for developing strategies to mitigate this emerging problem. Phylogenomic analyses of 227 genomes suggest that sepsis isolates are polyphyletic and closely related to both commensal and osteomyelitis isolate genomes. Pangenome analyses detect no gene acquisitions that distinguish all sepsis isolates. Core genome SNP analyses identify a number of mutations, affecting protein coding sequence, that are enriched in sepsis isolates. Analysis of the protein substitutions supports mutational origins of sepsis isolates.