Salmonella enterica is a gram-negative pathogen widely used to study host-pathogen interactions and innate immunity. While Salmonella enterica serovar Typhimurium has been the primary model for infection studies, S. enterica comprises over 2,500 serovars with diverse host specificity, pathogenesis, and virulence. Notably, S. enterica serovar Enteritidis has emerged as the most commonly isolated strain worldwide and a frequent cause of systemic salmonellosis in sub-Saharan Africa. Its ability to asymptomatically persist in poultry contributes to foodborne transmission, yet studies on host immune responses to S. Enteritidis remain limited.Programmed cell death is a crucial immune defense mechanism. Research on S. Typhimurium has shown that macrophages detect Salmonella and initiate pyroptosis via caspase-1 and caspase-11 activation. These caspases trigger Gasdermin-D pore formation, leading to cytokine release and cell death. However, most studies rely on the S. Typhimurium SL1344 strain, which has a histidine auxotrophy mutation affecting intracellular replication. The impact of intracellular replication on innate immunity remains unclear. Here, we describe a previously unrecognized apoptotic pathway activated by Salmonella Pathogenicity Island-2 and intracellular replication. This pathway requires caspase-8, RIPK1 kinase activity, and the apoptotic pore protein Pannexin-1, occurring independently of pyroptosis. Mechanistically, we show that replicating Salmonella induces TNF secretion in a TLR-dependent manner, and caspase-8-mediated apoptosis requires TLR4. We extend these findings to murine models of infection models using a persistent strain of S. Enteritidis. In mice, caspase-8, RIPK1, and TNF play essential roles in bacterial control and host survival. Mice lacking caspase-8 or TNF receptor succumb to infection despite expressing caspases-1 and -11, demonstrating the necessity of both apoptotic and pyroptotic pathways. Moreover, deletion of apoptotic and pyroptotic pores compromises bacterial clearance, highlighting their dual role in host defense. These findings refine our understanding of macrophage responses to Salmonella, revealing complex interactions between apoptosis, pyroptosis, and innate immunity. This study provides a framework for investigating diverse Salmonella serovars and developing targeted therapies for systemic infections.