Streptococcus dysgalactiae subspecies equisimilis (SDSE) is a Gram-positive bacterial pathogen that infects humans and is closely related to group A streptococcus (GAS). Compared with GAS, far less is known about SDSE pathobiology. Increased rates of invasive SDSE infections have recently been reported in many countries. One SDSE emm type (stG62647) is known to cause severe diseases, including necrotizing soft-tissue infections, endocarditis, and osteoarticular infections. To increase our understanding of the molecular pathogenesis of stG62647 SDSE isolates causing human infections, we sequenced to closure the genomes of 120 stG62647 SDSE isolates. The genomes varied in size from 2.1 to 2.24 Mb pairs. The great majority of stG62647 isolates had IS1548 integrated into the silB gene, thereby inactivating it. Regions of difference, such as mobile genetic elements, were the largest source of genomic diversity. All 120 stG62647 isolates were assayed for virulence using a well-established mouse model of necrotizing myositis. An unexpectedly wide range of virulence was identified (20% to 95%), as assessed by near-mortality data. To explore the molecular mechanisms underlying virulence differences, we analyzed RNAseq transcriptome profiles for 38 stG62647 isolates (comprising the 19 least and most virulent) grown in vitro. Genetic polymorphisms were identified from whole-genome sequence data. Collectively, the results suggest that these SDSE isolates use multiple genetic pathways to alter virulence phenotype. The data also suggest that human genetics and underlying medical conditions contribute to disease severity. Our study integrates genomic, mouse virulence, and RNAseq data to advance our understanding of SDSE pathobiology and its molecular pathogenesis.This study integrated genomic sequencing, mouse virulence assays, and bacterial transcriptomic analysis to advance our understanding of the molecular mechanisms contributing to Streptococcus dysgalactiae subsp. equisimilis emm type stG62647 pathogenesis. We tested a large cohort of genetically closely related stG62647 isolates for virulence using an established mouse model of necrotizing myositis and discovered a broad spectrum of virulence phenotypes, with near-mortality rates ranging from 20% to 95%. This variation was unexpected, given their close genetic proximity. Transcriptome analysis of stG62647 isolates responsible for the lowest and highest near-mortality rates suggested that these isolates used multiple molecular pathways to alter their virulence. In addition, some genes encoding transcriptional regulators and putative virulence factors likely contribute to SDSE emm type stG62647 pathogenesis. These data underscore the complexity of pathogen-host interactions in an emerging SDSE clonal group.