Author Summary During a bacterial infection, the innate immune response plays two critical roles: controlling early bacterial replication and stimulating the adaptive immune response to clear infection. Host recognition of bacterial components occurs through pathogen sensors at the cell surface or within the host cell cytosol. Inhibitor of apoptosis proteins (IAPs) have been recently implicated in immune regulation, but how IAPs contribute to immunity is incompletely understood. Here, we show that X-linked IAP (XIAP) protects against infection by the cytosolic bacterial pathogen, Listeria monocytogenes, which causes severe disease in neonates and immunocompromised individuals. We found that XIAP enhanced MAP kinase signaling in L. monocytogenes infected macrophages, a key innate immune effector cell. Additionally, XIAP enabled synergy between cell surface and cytosolic bacterial sensors, promoting increased gene expression of proinflammatory cytokines. Our findings suggest that IAPs are integral regulators of innate immune signaling, coordinating extracellular and intracellular responses against microbial components to control bacterial infection.