The first wave of host innate immune response to bacterial invasion is central to protection against microbial pathogens. Identification of the critical local mediators in the lung that provide early protection against bacteria is essential for a complete understanding of the molecular mechanism(s) underlying host defense. In an acute model of Streptococcus pneumoniae TIGR4 (SP-TIGR4) lung infection, we found MMP2 and MMP9 double null (MMP2/9-/-) were more susceptible to death when compared to wild type (WT) mice. In response to SP-TIGR4 challenge, MMP2/9-/- mice recruited more polymorphonuclear cells (PMNs) to the lung, however lungs and spleens isolated from the infected mice showed higher systemic bacterial load in the absence of MMP2 and MMP9. Consistent with an increase in lung PMNs, MMP2/9-/- mice showed significant increase in levels of IL-17, IP-10 and RANTES in BAL fluid. In vitro studies showed MMP2 mediated inhibited function of IL-17A proinflammation and MMP9 was related to ineffective bacterial phagocytosis and opsonization of PMNs. Taken together, these data support a protective role for MMP2 and MMP9 in host immune responses in early phase of bacterial infection.