Pien-Tze-Huang (PZH) is a popular traditional Chinese medicine (TCM) formula in China, but its pharmacokinetics has not been investigated yet. To better study the pharmacokinetic behaviors of PZH, an optimal ultraperformance liquid chromatography with triple quadrupole mass spectrometry (UPLC–MS/MS) method was developed for rapid quantification of six compounds (notoginsenoside R1, ginsenosides Re, Rg1, Rb1, Rd, and muscone) in rat plasma after oral administration of PZH. All analytes were extracted by protein precipitation with acetonitrile and separated on a Waters Acquity Cortecs C18 column within 3.9 min, and detected by multiple-reaction monitoring in positive ion mode. This proposed method exhibited good linearity (r≥0.9932) with a lower quantification limits of 0.558–1.566 ng/mL for all analytes. The intra- and inter-day precisions were within 8.24%, and the accuracy was within −10.05 to 9.87% for each analyte. The extraction recovery for each analyte ranged from 80.02 to 96.12%. This UPLC–MS/MS method was successfully applied to the pharmacokinetic study for PZH in rats.