CONTEXT: Zexie Decoction (ZXD) is a classical traditional Chinese medicine prescription that has long been used for the treatment of hyperlipidemia. However, its material basis and underlying mechanisms remain unclear. OBJECTIVE: This research aims to explore the effective compounds and lipid-lowering mechanism of ZXD in the treatment of hyperlipidemia by integrating serum pharmacochemistry, network pharmacology and targeted lipidomics. MATERIALS AND METHODS: A high-fat diet-induced hyperlipidemia mouse model was established for evaluating the therapeutic efficacy of ZXD. The absorbed components of ZXD in serum were identified using ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS). Network pharmacology analysis based on in vivo absorbed components was subsequently performed to construct molecular networks and predict potential mechanisms. Furthermore, targeted lipidomics was employed to characterize lysophospholipid metabolic changes associated with ZXD treatment for hyperlipidemia. RESULTS: Pharmacodynamic evaluation demonstrated that ZXD exerted significant lipid-lowering effects on hyperlipidemic mice. Serum pharmacochemistry analysis identified twelve absorbed constituents, including 3 prototype compounds and 9 metabolites. Network pharmacology analysis demonstrated that ZXD primarily modulated lipid metabolism-associated pathways, particularly the peroxisome proliferator-activated receptor (PPAR) signaling pathway and the lipid and atherosclerosis pathways. Molecular docking further revealed strong binding affinities between the major bioactive compounds of ZXD and key targets PPARA and PPARG. In addition, targeted lipidomics identified 36 lysophospholipid biomarkers associated with ZXD-mediated amelioration of hyperlipidemia. DISCUSSION AND CONCLUSIONS: Integrated analysis indicates that ZXD alleviates hyperlipidemia in association with modulation of the PPAR signaling pathway and lysophospholipid metabolism, highlighting a potential lysophospholipid-PPAR regulatory mechanism.