In our study, TLR4 expression in the hippocampus of mice w also stimulated by LPS, and it was found that TLR4 can reverse the inhibition of n‐3 PUFAs on the depressive behavior, inflammatory response, neuronal damage, and microglia activation of depression mice, which suggests that depression‐like behavior and hippocampal neuroinflammation in mice may be improved by n‐3 PUFAs through suppressing TLR4 pathway. This evidence concerns the gene TLR4 and major depressive disorder.