Significance Infants born prematurely suffer the greatest incidence of and impact from sepsis among all age groups. Therapeutic interventions aimed at reducing morbidity and mortality in this vulnerable population have been unsuccessful. Interleukin (IL)-18 is a proinflammatory member of the IL-1 superfamily. Serum IL-18 concentrations in uninfected premature infants are increased as compared with healthy adults. We show that IL-18 in the setting of sepsis results in gut injury, a potentiation of the host’s inflammatory response, increased bacteremia, and mortality mediated by IL-1 receptor 1 (IL-1R1)–dependent IL-17A produced by γδT and myeloid cells. The discovery of this novel IL-18/IL-1R1/IL-17A axis brings new hope for therapeutic interventions that target downstream IL-17A and ultimately reduce the increased mortality from sepsis in this understudied population.