Neuroinflammation is crucial for chronic stress-induced emotional disturbances. Stress-induced microglial activation occurs in selective brain regions (e.g., medial prefrontal cortex (mPFC)), but not in the others (e.g., nucleus accumbens (NAc)) and is sensitized with repetition of the stress. However, the mechanism remains unknown. Here we analyzed genome-wide patterns of social defeat stress-induced epigenetic and transcriptional changes in mPFC and NAc microglia. Before the stress, microglia in the two brain regions showed similar patterns of H3K27 acetylation in super-enhancers. The patterns diverged after the single stress and even more after the repeated stress. Some super-enhancers immediately responded to the stress specifically in the mPFC, whereas other super-enhancers gradually responded with repetition of the stress in both the two brain regions. These respective types of super-enhancers enriched different transcription factor binding motifs in their nucleosome-free regions. Furthermore, these epigenetic responses were concordant with the expression of adjacent genes associated with different biological functions. These findings show that stress induces multiple epigenetic regulations in microglia, which may contribute to the spatiotemporal patterns of neuroinflammation for emotional disturbances.