Compound Huanggen Granules (CHG), a traditional Chinese medicine (TCM) hospital preparation, has long been used in clinical practice for the prevention and treatment of liver fibrosis. However, due to the lack of in vitro chemical and in vivo metabolism studies, its pharmacodynamic material basis is still unrevealed. In this study, an analytical strategy integrating ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MSE) method and data post-processing strategy based on a self-built in-house components database was established and utilized for the rapid characterization of the multi-constituents of CHG and prototypes in cynomolgus monkey plasma after oral administration. As a result, a total of 81 compounds, including 14 phenolic acids, 6 coumarins, 25 flavonoids, 5 anthraquinones, 5 phenylpropanoids, 15 triterpenoid saponins, and 11 other ones, were plausibly or unambiguously identified on the basis of their accurate masses, and MS/MS fragments analysis, and also by comparison of RT and MS data with those of reference standards. In the in vivo study, according to the extracted ion chromatograms (EICs), 34 absorbed prototypical components were identified in cynomolgus monkey plasma after oral administration of CHG. It was demonstrated that the data post-processing strategy applied in this study could greatly enhance the structural identification efficiency, and the results obtained might be helpful for further studies on the quality control, pharmacokinetics and pharmacodynamics of CHG.