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Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is an herbal medicine for restoring yang from collapse. However, the multiregional neurotoxicity of Fuzi was unclear. This work was designed to discover the multiregional neurotoxicity-associated metabolic alterations induced by Fuzi in brain of rat. Fuzi-distributed components in cerebrospinal fluid and multiple brain regions were analyzed by using ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF-MS). The multiregional neurotoxicity including hippocampus, striatum and cerebellum was evaluated by behavioral tests, biochemical examinations, Hematoxylin/eosin (H&E), Nissl staining, TUNEL staining, reactive oxygen species and metabolomic analyses. Both cerebrospinal fluid metabolomics and the multiregional target tissue (hippocampus, striatum and cerebellum) metabolomics of the brain, based on UHPLC-QTOF-MS, were conducted to reveal the metabolic changes associated with Fuzi neurotoxicity. 13, 11, 11 and 8 ingredients of Fuzi were distributed into the cerebrospinal fluid, hippocampus, striatum, and cerebellum, respectively. Fuzi exposure could cause motor dysfunction and anxiety-like behaviors and decrease the level of brain derived neurotrophic factor (BDNF) and increase the level of neuron specific enolase (NSE). Fuzi exposure produced oxidative stress, neuronal lesions, neuronal apoptosis and metabolic alterations, which produced the multiregional neurotoxicity in the brain. The differentially expressed metabolites associated with Fuzi exposure in the cerebrospinal fluid, hippocampus, striatum and cerebellum predominantly involved glycerophospholipid metabolism, sphingomyelin metabolism, arachidonic acid metabolism, purine metabolism, amino acid metabolism, TCA cycle and fatty acid β-oxidation. Fuzi exposure produced the multiregional neurotoxicity in the hippocampus, striatum and cerebellum of the brain.