Fine particulate matter (PM2.5) has been reported to be associated with neurological disorders. However, the effects of PM2.5 on changes in metabolic and lipid profile of the brain are unclear. In this study, global metabolomics and lipidomics in mice cortex were investigated from the analyses by ultraperformance liquid chromatography-Orbitrap mass spectrometry. The partial least-squares discriminant analysis showed that the metabolite and lipid profiles were significantly altered by PM2.5 exposure. The changed metabolic pathways including alanine, aspartate, and glutamate metabolism, carnitine metabolism, and glycerophospholipid remodeling pathway were found to be associated with a neurodegenerative process according to their corresponding molecular mechanisms. Our results indicated that PM2.5 exposure could induce neurological damage.