Sepsis is an acute systemic inflammatory response to infection associated with high morbidity and mortality. Recent studies have indicated that depletion of MAIT cells is associated with the development of secondary infections in septic patients. Here, we aimed to investigate the mechanisms by which MAIT cells contribute to sepsis pathology. We evaluated immune responses in C57BL/6 wild type (WT) or MHC-related-molecule I whole body knock-out (MR1-KO) mice using the cecal ligation and puncture (CLP) model of polymicrobial sepsis. We found that sepsis-induced mortality was significantly increased in MR1-KO mice compared to WT mice (p = 0.003). When lung and serum cytokine levels were assessed in these mice, levels of IL-1α, IL-1β, TNF-α, IL-27, IL-17A, IFN-β and GM-CSF in lungs, but not serum, were found to be lower in MR1-KO mice compared to WT mice. Our data suggest that MAITs may be important for protection against sepsis and that MAITs may contribute to lung-specific cytokine responses and protection against secondary infections. Furthermore, our studies in humans indicates that IFN-γ and IL-17A cytokine expression in peripheral MAIT cells are decreased in patients with severe sepsis at day 1 of illness as compared to that of day 90 and age-matched healthy controls. Insights from both mice and human studies will improve our understanding of MAIT cell function during sepsis, and highlight therapeutic potentials of MAIT cells in sepsis.