Salmonella enterica is a Gram-negative, facultative intracellular pathogen transmitted through contaminated food and water and remains a major global public health threat. The species is extraordinarily diverse, comprising more than 2,600 distinct serovars, which occupy a wide range of ecological and host niches. S. enterica is estimated to cause 100–400 million infections and up to 950,000 deaths each year, resulting in substantial morbidity, mortality, and economic burden. Despite this, no vaccine currently provides protection across the diversity of clinically relevant Salmonella serovars. Using a murine model of salmonellosis, we demonstrated that four conserved surface antigens confer partial protection when administered individually. We demonstrated that humans were capable of mounting an immune response ot these antigens during natural infection, during experimental human infection, and after immunisation with outer membrane vesicles-based vaccines (GMMA). Reductions in bacterial burdens were comparable to those achieved with GMMA currently in industrial development. Strikingly, when combined into a multivalent formulation, these antigens provided significantly enhanced protection against both S. Typhimurium and S. Enteritidis, demonstrating multi-serovar efficacy. Notably, co-administration of these antigens with GMMAs resulted in near-complete protection, with mice surviving for months following lethal challenge and vaccine performance was further improved by formulation with alum and Salmonella.