A sensitive and specific liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS/MS) method was developed and validated to simultaneously quantify 11 active compounds (coptisine, jatrorrhizine, berberine, palmatine, baicalin, baicalein, wogonoside, wogonin, rhein, emodin and aloeemodin) from Xiexin decoction (XXD) in rat plasma. Plasma samples extracted by a single-step protein precipitation procedure were separated using the gradient mode on a Dikma ODS-C₁₈ column. Selected reaction monitoring scanning was employed for quantification with switching electrospray ion source polarity between positive and negative modes in a single run. Calibration curves offered satisfactory linearity (r > 0.995) at linear range of 0.47-60 ng/mL for coptisine, jatrorrhizine, berberine and palmatine, 15-1930 ng/mL for baicalin, 20-2560 ng/mL for baicalein, 14-1790 ng/mL for wogonoside, 0.57-72.8 ng/mL for wogonin, 10-1280 ng/mL for rhein, 0.6-76.8 ng/mL for emodin and 3.0-384 ng/mL for aloeemodin. The intra- and interday precisions were less than 10.2% in terms of relative standard deviation (RSD), and the accuracies were within ±10.84% in terms of relative error (RE). It was successfully applied to the evaluation of pharmacokinetics after single oral doses of XXD were administered to rats.