UHPLC combined with Fourier-transform ion cyclotron resonance MS metabonomic approach was employed to screen the differential components between normal rats and yeast-induced pyrexia rats after an oral administration of Gegenqinlian decoction (GQLD). Nine compounds, namely puerarin, daidzein, baicalin, wogonoside, wogonin, berberine, palmatine, jateorhizine, and coptisine, were identified as differential components in the plasma. A rapid, sensitive, selective, and accurate UHPLC-MS method was developed and fully validated for the simultaneous determination of the screened components in rat plasma after an oral administration of GQLD. The values for the limit of quantification ranged from 0.025 to 5.0 ng/mL. The inter- and intra-day precision of all analytes was </=10.7%, with an accuracy of </=10.5%. Good extraction recovery and matrix effects were also obtained. The method was successfully applied to a comparative pharmacokinetic study of GQLD in normal and pyrexia rats. The results showed that the pharmacokinetic behavior of the analytes was changed in pyrexia rats compared to normal rats. These results could provide beneficial guidance for clinical applications of GQLD. CI - (c) 2021 John Wiley & Sons, Ltd.