Atmospheric particulate matter (PM), a ubiquitous air pollutant, is the leading environmental risk factor for mortality worldwide. Experimental and epidemiological studies consistently suggest a strong link between long-term exposure to PM_2.5 (<2.5 μm, fine PM) and cognitive impairment. The neuroinflammatory response is presumed to be one of the main mechanisms of PM_2.5-induced cognitive impairment, possibly leading to synaptic dysfunction. However, the main route and mechanism underlying the cause of cognitive dysfunction and pathogenic alterations in PM_2.5-exposure mice remain poorly understood. Therefore, this study aimed to investigate the main route and mechanism of PM_2.5-induced cognitive impairment. Our results showed that PM_2.5 directly entered the brain following nasal administration, and both the short-term PM_2.5 administration via atomization and nasal drops induced learning and memory impairments and neuronal damage in adult mice. Moreover, astrocytes and microglia were both activated in the two short-term PM_2.5exposure models, while few changes in the inflammatory response were observed in the peripheral circulatory system. Furthermore, a further transcriptional analysis revealed that short-term PM_2.5administration led to cognitive impairment mainly by modulating synaptic functions and that although glia were activated, the glia-related pathological pathways were not significantly activated. Notably, following PM_2.5 exposure, PLX3397-induced microglial deletion did not restore the cognitive function of the mice. In conclusion, our results provide evidence that PM_2.5 enters the brain via the nose-to-brain route to impair cognitive function, and short-term exposure to PM_2.5 directly alters synaptic function rather than the neuroinflammatory response to affect cognition.