Exposure to PM_2.5 is associated with an increased incidence of CNS diseases in humans, as confirmed by numerous epidemiological studies. Animal models have demonstrated that PM_2.5 exposure can damage brain tissue, neurodevelopmental issues and neurodegenerative diseases. Both animal and human cell models have identified oxidative stress and inflammation as the primary toxic effects of PM_2.5 exposure. However, understanding how PM_2.5 modulates neurotoxicity has proven challenging due to its complex and variable composition. This review aims to summarize the detrimental effects of inhaled PM_2.5 on the CNS and the limited understanding of its underlying mechanism. It also highlights new frontiers in addressing these issues, such as modern laboratory and computational techniques and chemical reductionism tactics. By utilizing these approaches, we aim to fully elucidate the mechanism of PM_2.5-induced neurotoxicity, treat associated diseases, and ultimately eliminate pollution.