Previous studies have suggested that neonates rely heavily on innate immunity for their antimicrobial response to bacterial infections. However, the innate immune response by neonates to bacterial infection remains poorly characterized. Here, we show that in a murine model of neonatal polymicrobial sepsis, CXC ligand 10 (CXCL10) concentrations increase in the blood and peritoneum concordant with the peritoneal recruitment of granulocytes and macrophages. Additionally, CXC receptor 3 (CXCR3) expression on elicited peritoneal macrophages and granulocytes increases following sepsis. Blockade of CXCL10 worsens not only recruitment and phagocytic function of peritoneal granulocytes and macrophages but also survival. Deletion of CXCR3 also significantly increases mortality to a septic challenge. Finally, we demonstrate that the protective adjuvant effect of pretreatment with a Toll-like receptor 4 agonist to neonatal sepsis is dependent on an endogenous CXCL10 response and that pretreatment of neonates with CXCL10 can also significantly improve macrophage and granulocyte function and modestly improve outcome to polymicrobial sepsis. Together, these data suggest a critical role for CXCL10 signaling during neonatal sepsis.