AbstractChronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic‐lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic‐lysosomal pathway, leading to microglial polarization towards anti‐inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia in vitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic‐lysosomal activation in hypoperfusion‐induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.image