Background: Huan Nao Yi Cong decoction (HYD) is a compound Chinese medicine with clinical application in the treatment of Alzheimer's disease (AD), by delaying its pathological progress.This work aimed to test whether HYD affects lipid metabolism by regulating the expression of metabolic enzymes, delaying the pathological process of AD and preventing hepatic damage caused by Polygonum multiflorum Radix Preparata (PMRP). Methods: The main components in HYD were determined by high performance liquid chromatography(HPLC). Double transgenic APP/PS1 mice were administrated intragastric for 24w. At 8w, 16w, 24w, the hepatic injury and pathological changes in hippocampal C1 area of APP/PS1 double transgenic mice were investigated by assessment of serum biochemical parameters, histopathology and terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL) methods. Ultra-performance liquid chromatography in the form of Quanfirmation-Exactive Mass Spectrometry/Mass Spectrometry (UPLC-Q-Exactive MS/MS) was used to study changes in lipid metabolism in hepatic and brain tissues. Metabolic enzyme expression was assayed using immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and Western blot. Results: Both Polygonum multiflorum Radix (PMR) and PMRP induced hepatic damage 8 weeks after administration. In contrast, HYD showed reduced hepatic injury as it regulated 31 hepatic injury-related biomarkers associated with phospholipid and sphingolipid metabolic pathways by tuning the expression of acid phospholipase A2 (cPLA2), phosphatidylphosphatase (PAP), and diacylglyceride acyltransferase2 (DGAT2). HYD also affected the expression of 32 AD biomarkers related to phospholipids and sphingomyelin metabolic pathways by regulating the expression of phospholipase D2 (PLD2), choline ethanolamine phosphotransferase (CEPT1), sphingomyelin phosphodiesterase1 (SMPD1), thereby improving the brain tissue pathological changes. Conclusion: Our research not only used lipidomics to analyze the toxicity-inducing mechanism of PMR and PMRP, but also showed that HYD administration in vivo alleviated hepatic damage compared to using PMR and PMRP alone and can improve the behavioral and pathological features of AD mice.