Staphylococcus pseudintermedius is the foremost cause of opportunistic canine skin and mucosal infections worldwide. Multidrug-resistant (MDR) and methicillin-resistant Staphylococcus pseudintermedius (MRSP) lineages have disseminated globally in the last decade and present significant treatment challenges. However, little is known regarding the factors that contribute to the success of MDR lineages. In this study, we compared the genome sequence of 110 UK isolates of S. pseudintermedius with 2166 genomes of S. pseudintermedius populations from different continents. A novel core genome multi-locus typing scheme was generated to allow large-scale, rapid and detailed analysis of S. pseudintermedius phylogenies and was used to show that the S. pseudintermedius population structure is broadly segregated into an MDR population and a non-MDR population. MRSP lineages are predicted to encode certain resistance genes either chromosomally or on plasmids, and this is associated with their MLST sequence type. A comparison of lineages most frequently implicated in disease, ST-45 and ST-71, with the phylogenetically related ST-496 lineage that has a comparatively low disease rate, revealed that ST-45 and ST-71 genomes encode distinct combinations of phage-defence systems and concurrently encode a high number of intact prophages. In contrast, ST-496 genomes encode a wider array of phage defence systems and lack intact and complete prophages. These findings indicate that MRSP lineages have significant structural genomic differences and that prophage integration and differential antiviral systems correlate with the emergence of successful genotypes.