Salmonella is a leading cause of foodborne illness in the United States, yet rural–urban differences in incidence and their underlying drivers remain poorly characterized. We conducted an ecological analysis of deidentified probable and confirmed Salmonella cases from the National Notifiable Diseases Surveillance System (NNDSS), 2011–2023, to evaluate temporal, regional, and population-level determinants of Salmonella incidence. Multivariable negative binomial models assessed rural–urban differences nationally and by U.S. Census region, and Blinder–Oaxaca decomposition quantified contributions of demographic, socioeconomic, healthcare access, and health-related factors. Age-adjusted incidence was consistently higher in rural than in urban counties. After adjustment, rural counties had higher incidence nationally and separately in all four regions (Northeast, Midwest, West, and South). County-level factors explained 66% of the national rural–urban gap, driven primarily by age structure, income, education, and food environment. Adults aged ≥65 years accounted for approximately 60% of the explained difference and were the dominant contributor in some regions. Regional variation was evident, with age predominating in the Midwest and West and education contributing more in the Northeast and South. A substantial unexplained component remained. These findings highlight persistent, regionally heterogeneous disparities and underscore the need for targeted, region-specific surveillance and prevention strategies.