This study investigates host-specific interactions between Salmonella Gallinarum and macrophages from chicken and cattle, compared with the broad host range serovar S. Typhimurium and the cattle-adapted S. Dublin. S. Gallinarum showed reduced macrophage uptake, low cytotoxicity, and attenuated pro-inflammatory responses, together with host-dependent intracellular survival and differential Toll-like receptor regulation. These findings suggest a host-adapted strategy favoring intracellular persistence and contribute to understanding the mechanisms underlying Salmonella host specificity.