Invasive non-typhoidal Salmonella (iNTS) infections represent a significant public health concern, particularly in sub-Saharan Africa, where they are a leading cause of bloodstream infections, associated morbidity, and mortality, especially in children and immunocompromised individuals. Unlike the more commonly recognized diarrheal form of Salmonella infection, iNTS infections typically present with bacteremia, often without gastrointestinal symptoms. The rapid emergence of multidrug-resistant (MDR) iNTS serovars further complicates treatment, limiting therapeutic options and increasing the risk of adverse outcomes. MDR iNTS are currently recognised by WHO, CDC as well as the Australian and UK Government as high-priority pathogens that cause extraordinary medical challenges and urgently require novel therapies. Despite the increase in prevalence of MDR iNTS globally, along with a growing understanding of their genomes, there is limited research defining the specific bacterial and host factors associated with currently circulating pathogen lineages. To address this, we have capitalised on unprecedented access to clinical isolates through our collaborators to overcome the use of prototypic laboratory strains which do not reflect currently circulating and rapidly evolving MDR iNTS. Here we evaluated two globally prevalent iNTS; ST34 monophasic S. Typhimurium (ST34) and S. Dublin (ST10 and ST74) and showed that ST34 and ST74 isolates replicate extremely efficiently in host macrophages and induce unique host responses, vastly different from the prototype S. Typhimurium SL1344 (ST19) which is often used to study NTS, generally. We aim to utilise this information to identify unique host processes that may be targeted for treatment of serious infections. Understanding the epidemiology, pathogenesis, clinical manifestations, and treatment options for iNTS infections is crucial for effective prevention and management strategies, particularly in regions with high disease burden.