Chronic social stress may lead to depression and elevated anxiety and is a risk for mental illness. We previously reported in mice that chronic social stress activates microglia in the medial prefrontal cortex (mPFC) through innate immune receptors TLR2/4, leading to neuronal dysfunctions and depression-related behaviors. It is reported that lipopolysaccharide, a TLR4 ligand, induces cytokine production from microglia in a left-right asymmetric manner. Thus, we speculate that chronic stress may induce asymmetric microglial responses in the mPFC. Here we found that chronic social stress induced left-right asymmetric changes of gene expression in mPFC microglia using laser microdissection microscopy followed by RNA sequencing. Gene ontology analysis revealed that the genes upregulated in microglia of the right, but not left, mPFC enriched immune response-related genes. These findings show that chronic stress induces left-right asymmetric neuroinflammation and paves the way for elucidating its roles and mechanisms for chronic stress-induced neural dysfunctions.