The aim of the present study was to determine the anti-inflammatory effect of IFN-τon endometritis using a mouse model ofS. aureus-induced endometritis and to elucidate the mechanism of action underlying these effects. In the present study, the effect of IFN-τonS. aureusgrowth was monitored by turbidimeter at 600 nm. IFN-τdid not affectS. aureusgrowth. The histopathological changes indicated that IFN-τhad a protective effect on uterus tissues withS. aureusinfection. The ELISA and qPCR results showed the production of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 was decreased with IFN-τtreatment. In contrast, the level of the anti-inflammatory cytokine IL-10 was increased. We further studied the signaling pathway associated with these observations, and the qPCR results showed that the expression of TLR2 was repressed by IFN-τ. Furthermore, the western blotting results showed the phosphorylation of IκB, NF-κB p65, and MAPKs (p38, JNK, and ERK) was inhibited by IFN-τtreatment. The results suggested that IFN-τmay be a potential drug for the treatment of uterine infection due toS. aureusor other infectious inflammatory diseases.