Salmonella Dublin is a host-adapted, invasive non-typhoidal Salmonella (iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Here, we characterised a global population of 1,303 S. Dublin isolates for resistance and virulence mechanisms using a combined approach of in silico and in vitro analyses. We observed distinct populations of Vi antigen-negative S. Dublin circulating in different geographical regions, with the emergence of a North American cluster ~60 years ago. Further, we identified two distinct lineages in Australia, within which we discovered a novel hybrid plasmid encoding both AMR and mercuric resistance, highlighting the potential for emerging virulent and resistant lineages. These differences, in addition to the lack of Vi flagella represent adaptation mechanisms that may enhance survival and pathogenicity, and in turn affect prevention and control strategies for future S. Dublin infections. Collectively, our study embodies one of the most comprehensive investigations of S. Dublin and highlights the potential impact of pathogen adaptation on global health and economic burdens experienced by different sectors including livestock and human health.