Previous studies indicate that exposure to zinc oxide nanoparticles (ZnO NPs) may potentially cause brain damage in mammals; however, the mechanism remains unclear. In particular, their effect on brain energy metabolism, which is essential for maintaining brain function, is unknown. This study demonstrates that intranasal exposure to ZnO NPs causes a decrease in the relative brain weight of rats and induces structural and pathological changes in the brain. Multiomics data consistently demonstrate the alteration of energy metabolism in the brain, including upregulated glycolysis, a downregulated tricarboxylic acid cycle, and oxidative phosphorylation, as well as downregulated fatty acid β-oxidation, an alternative pathway for an energy supply. As a result, the adenosine triphosphate (ATP) levels in the brain are depressed. ZnSO4 exposure results in similar Zn accumulation, identical Zn chemical species, and similar patterns of effects on the brain compared to ZnO NPs, suggesting that the effects observed in the ZnO NP group are mainly caused by the released Zn2+. This study provides the first in vivo evidence for compromised brain energy metabolism induced by ZnO NPs. Further studies are thus imperative to explore the longer-term consequences of the compromised brain energy metabolism and the origin of the toxic effects and to expand to other NPs.