NLRP3 inflammasome is a critical player in innate immunity. Neutrophil recruitment to tissues and effective function of neutrophils are critical innate immune function to bacterial clearance. However, the role of NLRP3 in neutrophil-dependent bacterial clearance in polymicrobial sepsis is unclear. Herein, we evaluated the role of NLRP3 in polymicrobial sepsis induced by cecal ligation and puncture (CLP). Our results exhibit protection from death in NLRP3-deficient ( Nlrp3 −/− ) and NLRP3 inhibitor-treated wild-type (C57Bl/6) mice. Both Nlrp3 −/− and NLRP3 inhibitor-treated mice displayed lower bacterial load albeit no impairment in neutrophil recruitment to peritoneum. However, neutrophil depletion abrogated protection from death of nd NLRP3-deficient ( Nlrp3 −/− ) mice in response to CLP. Intriguingly, Nlrp3 −/− peritoneal cells (primarily neutrophils) following CLP demonstrate decreased autophagy, augmented phagocytosis and enhanced scavenger receptor (MARCO) and mannose binding leptin (MBL) expression. These findings enhance our understanding of the critical role of NLRP3 in modulating autophagy and phagocytosis in neutrophils and suggest that therapies should be targeted to modulate both autophagy and phagocytosis in neutrophils to control bacterial burden in tissues during CLP-induced polymicrobial sepsis.