Most Salmonella serovars cause disease in many host species, while a few serovars have evolved to be host specific. Very little is known about the mechanisms that contribute to Salmonella host specificity. We compared the interactions between chicken primary macrophages (CDPM) and host-generalist serovar Salmonella enterica serovar Typhimurium, host-adapted Salmonella enterica serovar Dublin, and avian host-specific Salmonella enterica serovar Gallinarum. S. Gallinarum was taken up in lower numbers by CDPM than S. Typhimurium and S. Dublin; however, a higher survival rate was observed for this serovar. In addition, S. Typhimurium and S. Dublin caused substantially higher levels of cell death to the CDPM, while significantly higher concentrations of NO were produced by S. Gallinarum-infected cells. Global transcriptome analysis performed 2 h postinfection showed that S. Gallinarum infection triggered a more comprehensive response in CDPM with 1,114 differentially expressed genes (DEGs) compared to the responses of S. Typhimurium (625 DEGs) and S. Dublin (656 DEGs). Comparable levels of proinflammation responses were observed in CDPM infected by these three different serovars at the initial infection phase, but a substantially quicker reduction in levels of interleukin-1β (IL-1β), CXCLi1, and CXCLi2 gene expression was detected in the S. Gallinarum-infected macrophages than that of two other groups as infections proceeded. KEGG cluster analysis for unique DEGs after S. Gallinarum infection showed that the JAK-STAT signaling pathway was top enriched, indicating a specific role for this pathway in response to S. Gallinarum infection of CDPM. Together, these findings provide new insights into the interaction between Salmonella and the host and increase our understanding of S. Gallinarum host specificity.