Polygoni multiflori radix (PM) is a well-known tonic herb. It has been reported that PM could cause idiosyncratic inflammatory liver injury in some individuals. In this study, we investigated the mechanism of PM-induced idiosyncratic inflammatory liver injury in zebrafish and rat models based on pharmacodynamics and pharmacokinetics. The zebrafish were administered with polygoni multiflori radix extract (PME), emodin (EMO), and 2,3,5,4′-tetrahydroxystilbene-2-Ο-β-D-glucoside (TSG) after lipopolysaccharide (LPS) treatment, to establish an idiosyncratic inflammation model. In zebrafish with idiosyncratic inflammation, PME, EMO, and TSG decreased liver area and brightness and increased the number of immune cells around the colliculi. PME+LPS produced hepatocyte damage, aggravated mitochondrial and endoplasmic reticulum damage, and increased AST and ALT activity. RT-PCR showed that PME and EMO up-regulated the expression of IL-6, IL-1β, and INF-γ, and PME down-regulated expression of FXR and SHP. In rats with idiosyncratic inflammation, AST and ALT activities increased significantly, and liver tissues showed pathological damage. An efficient and sensitive LC-MS/MS method was established for the pharmacokinetic study of EMO and TSG in rats with idiosyncratic inflammation. The AUC_0−t was higher for EMO and TSG in the model group compared with the normal group. The MRT_0−t was significantly prolonged in EMO, while CL_z/F was significantly reduced. The present results suggested that the absorption of potentially toxic components of PM increased and metabolism slowed down under inflammatory stress, and PM induced idiosyncratic liver injury via the FXR-SHP axis.