Abstract: This study employed ultra-high performance liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap-MS), combined with the Compound Discoverer and Progenesis QI data processing platforms, to systematically analyze the chemical constituents of the complete classical famous prescription Xiayuxue Decoction, its single crude drugs, and its modified formulations (formulas without rhubarb, without peach kernel, and without Zhechong). The qualitative and semi-quantitative changes in chemical constituents after compatibility were investigated, and the mechanisms by which each herb affected the stability of the formula’s components were revealed, thereby providing a scientific basis for elucidating the compatibility principles of Xiayuxue Decoction. A systematic component analysis was conducted on the single medicinal herbs constituting Xiayuxue Decoction, namely rhubarb, peach kernel, and Zhechong, and a total of 99, 43, and 25 constituents were successfully identified from each herb, respectively. Subsequently, qualitative and multivariate statistical analysis was conducted on the whole decoction and three herb-depleted decoction (i.e., without rhubarb, without peach kernel, and without Zhechong). The results showed that 114, 49, 104, and 114 constituents were detected in the whole decoction, the decoction without rhubarb, the decoction without peach kernel, and the decoction without Zhechong, respectively. Furthermore, the results of multivariate statistical analysis indicated that rhubarb could significantly affect the dissolution of peach kernels and Zhechong components. Peach kernels could inhibit the dissolution of several anthraquinone and tannin components in rhubarb, which may alleviate the laxative side effects of rhubarb. Zhechong could promote the dissolution of active components in peach kernels while inhibiting the dissolution of anthraquinones and tannins in rhubarb, thus exhibiting a dual regulatory effect on the components of the whole decoction. In conclusion, the findings suggest that there are complex synergistic and antagonistic interactions among the three medicinal materials in Xia Yuexue Decoction, which jointly improve the therapeutic efficacy and reduce toxic and adverse effects. This study reveals the compatibility rules of Xiayuxue Decoction from the perspective of chemical constituent changes, overcoming the previous limitation of merely identifying the types of components. It enables the elucidation of qualitative and semi-quantitative dynamic patterns of chemical components after compatibility, thereby providing methodological references and theoretical support for research on the compatibility mechanisms of classical famous prescriptions.