The innate immune system provides the first line of defence against infection and senses microbial and host-derived danger signals through families of pattern recognition receptors (PRR). The NOD-like receptors (NLRs) are one such family of PRR with emerging roles in mediating host defence against infection as well as driving sterile inflammation. Activation of specific NLRs (e.g. NLRC4) leads to the assembly of signalling complexes called ‘inflammasomes’, which provide a molecular platform to trigger the activation of the protease, caspase-1. Upon activation, caspase-1 mediates the maturation and secretion of pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18, to coordinate host-protective inflammatory responses. NLRC4 recognises microbial motifs from pathogenic bacteria such as Salmonella Typhimurium, and NLRC4 inflammasome function is required for pathogen clearance. While the molecular function of the NLRC4 inflammasome is well appreciated, the cell types mediating NLRC4-dependent host responses during in vivo infection are unclear. Our data indicate that peritoneal macrophages provide the initial sensing of Salmonella in vivo, resulting in IL-1β production and inflammatory cell recruitment. Surprisingly, the recruited neutrophils provided a second wave of IL-1β production at the site of infection, enhancing neutrophil antimicrobial effector functions and culminating in effective pathogen clearance. Our study demonstrates neutrophils as a new cellular player in NLRC4 response and an elegant interplay between innate immune cells for co-ordinating inflammasome-dependent immune defense in vivo.