This study aims to perform a comprehensive multi-strategy screening of quality markers (Q-markers) by integrating serum pharmacochemistry, chromatographic fingerprinting, and network pharmacology. The objective is to apply these methodologies for the quality control of traditional Chinese medicine (TCM) compound preparations. Firstly, the UPLC-Q-Exactive Orbitrap-MS was used to conduct a comparative analysis of the aqueous extract of Di Huang Yin Zi (DHYZ), the blank group, and the dosing group. Through the Xcalibur software, 10 blood components and 17 metabolites absorbed by DHYZ were identified. Then, the HPLC acetonitrile-formic acid water gradient elution system was used for detection at 330 nm. HPLC analysis was conducted on 16 batches of samples, and 22 common peaks with a similarity greater than 0.9 were established. 8 qualitative chemical components were quantitatively analyzed. Including morroniside, loganin, echinacoside, 5-hydroxymethylfurfural, acteoside, cinnamaldehyde, polygalaxanthone III and 3,6'-disinapoyl sucrose. The sample quality was comprehensively evaluated by using cluster analysis (HCA), Principal component analysis (PCA), and Orthogonal partial least squares discriminant Analysis (OPLS-DA). The results show that the 16 batches can be divided into 4 categories, and the results of PCA and HCA are consistent. The OPLS-DA model is stable and reliable, identifying morroniside (peak 4), echinacoside (peak 9), acteoside (peak 11), and 3,6'-disinapoyl sucrose (peak 13) as key discrimination markers. Finally, using network pharmacology methods, we constructed a component-target-disease-pathway network, thereby identifying 27 components associated with the efficacy of DHYZ. By integrating the above results, 3 active ingredients, morroniside, echinacoside, and 3,6'-disinapoyl sucrose, were identified as Q-markers that can be used for the quality control of DHYZ, providing a reference for establishing a robust quality control system for DHYZ.