Abstract: The traditional sedative-hypnotic Chinese medicine semen ziziphi spinosae (SZS) has been widely used to treat neuroinflammation-related diseases in recent years. However, its anti-neuroinflammatory mechanism at the metabolomic level remains incompletely understood. The present study explored the protective mechanisms of SZS against lipopolysaccharide (LPS)-induced neuroinflammation based on metabolomics and Western blot analysis. The results demonstrated that SZS significantly ameliorated LPS-induced pathological damage, oxidative stress, and inflammatory responses in rat cerebral cortex. A total of 28 differential metabolites were identified in rat serum and brain, which were primarily enriched in the glycerophospholipid metabolism pathway. Western blot analysis confirmed that SZS firstly regulated key metabolic molecules, then activated peroxisome proliferator-activated receptor γ (PPAR-γ). PPAR-γ suppressed the TLR-4/NF-κB signaling pathway, and thereby produced anti-neuroinflammatory effects. Molecular docking results revealed that spinosin, jujuboside, and coclaurine in SZS formed strong interactions with PPAR-γ, IκB-NF-κB, TLR-4, and iNOS via hydrogen bonding at multiple amino acid sites. In summary, SZS exhibited anti-neuroinflammatory effects at the metabolic level, which provides support for its clinical application in central neuroinflammation treatment.