Repeated environmental stress induces neural inflammation along with depression and increased anxiety. Innate immune molecules such as toll-like receptors (TLR) recognize exogenous and endogenous ligands to provoke inflammatory response. In this study, we found that social avoidance and elevated anxiety induced by social defeat stress was abolished in TLR2 and TLR4 double knockout mice. These mice neither exhibited decreased neuronal response, neuronal dendrite retraction, nor changes in microglia activity observed in medial prefrontal cortex (mPFC) of wild-type mice. TLR2 and TLR4 knockdown specifically in mPFC microglia suppressed repeated social defeat stress induced-social avoidance.. Repeated social defeat stress increased interleukin-1α and TNF-α expression in mPFC microglia in TLR2 and TLR4 dependent manner. Inhibition of these inflammatory cytokines by neutralizing antibodis in mPFC reduced social avoidance induced by social defeat stress. These results demonstrated that repeated social defeat stress evoked microglial activation in mPFC through TLR2 and TLR4, and released inflammatory cytokines induced social avoidance presumably through neuronal changes.