IL-18 is a unique cytokine that exerts both pro- and anti-inflammatory effects depending on the surrounding environments. Excessive inflammation in the feto-maternal interface is thought to result in the onset of miscarriage and preterm birth, but much is unknown about the function of IL-18 in pregnancy. Here, we report the protective role of IL-18 in pregnancy using lipopolysaccharide (LPS)-induced murine miscarriage models. Whereas a low dose (1 µg) of LPS injection in pregnant mice did not induce miscarriages, the additional injection of anti-IL-18 neutralizing antibody (IL-18 nAb) resulted in a significant increase in abortion rates among the pregnant mice. Under these conditions, multiple T-cell subsets and natural killer cells produced significantly lower levels of the type 1 cytokine IFN-γ and the type 2 cytokine IL-4. The miscarriage induced by the low-dose LPS along with the IL-18 nAb was improved by the supplementation of IFN-γ and IL-4. Furthermore, the main source of IL-18 production was found to be the myometrium rather than macrophages. These results indicated that IL-18, which was initially thought to have a harmful effect on the maintenance of pregnancy, has a protective role in miscarriage against minor stimulation by pathogens with modulating immune homeostasis.