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Diabetes increases the occurrence and severity of atherosclerosis. When plaques form in brain vessels, cerebral atherosclerosis causes thickness, rigidity, and unstableness of cerebral artery walls, leading to severe complications like stroke and contributing to cognitive impairment. So far, the molecular mechanism underlying cerebral atherosclerosis is not determined. Moreover, effective intervention strategies are lacking. In this study, we showed that polarization of microglia, the resident macrophage in the central nervous system, appeared to play a critical role in the pathological progression of cerebral atherosclerosis. Microglia likely underwent an M2c-like polarization in an environment long exposed to high glucose. Experimental suppression of microglia M2c polarization was achieved through transduction of microglia with an adeno-associated virus (serotype AAV-PHP.B) carrying siRNA for interleukin-10 (IL-10) under the control of a microglia-specific TMEM119 promoter, which significantly attenuated diabetes-associated cerebral atherosclerosis in a mouse model. Thus, our study suggests a novel translational strategy to prevent diabetes-associated cerebral atherosclerosis through in vivo control of microglia polarization.