European foulbrood (EFB) is an increasingly prevalent honey bee disease. While the genetic diversity of the causative agent, Melissococcus plutonius, and microbial ecological factors have been proposed to play a role in EFB severity, the roles of these elements remain unclear. To better characterize drivers of disease, we first compared the genotypic and phenotypic traits of M. plutonius strains relevant to pathogenicity. Despite infection-derived M. plutonius strains having a largely similar host-adapted pangenome, strain-level variance in plasmid presence, secondary metabolite production, in vitro antimicrobial resistance, and in vitro aerotolerance was seen. M. plutonius strains of typical and atypical phylotypes were assessed for inter-strain interactions, in which interaction resulted in strain-dependent effects on growth, and in vivo, the development of strain dominance or exclusion was seen. These findings suggest that M. plutonius virulence and fitness capacity arise from the dynamic interplay between strain-specific physiology and ecological circumstances, and reveal, overall, that the course of EFB is shaped by the intertwined effects of genetic capacity, microbial interactions, and ecological context, rather than by any single factor.