BACKGROUND: Trichiosanthis Pericarpium (TP) is the dried ripe peel of Trichosanthes kirilowii Maxim., also known as gualoupi in Chinese, effectively clears heat and transforms phlegm. Traditional Chinese medicine (TCM) prescriptions that contain TP are widely used in clinical practice to treat respiratory diseases, including chronic obstructive pulmonary disease (COPD). However, the active ingredients of TP and the potential targets and mechanisms of action of TP against COPD have not been sufficiently investigated. PURPOSE: This study aimed to determine the active ingredients of TP and the potential targets and mechanisms of action of TP against COPD. STUDY DESIGN: The initial phase comprised the screening of potential active ingredients in TP, this was followed by the evaluation of their pharmacodynamic effects through both in vivo and in vitro experiments. Subsequently, network pharmacology and molecular docking were utilized to predict the key targets and associated pathways, which were later validated through animal-related experiments. Finally, the pharmacodynamic basis of TP interacting with the relevant target was identified using surface plasmon resonance (SPR). METHODS: The potential active ingredients of TP were predicted by serum chemical composition analysis. The pharmacodynamic effect of Total Flavonoids of Trichiosanthis Pericarpium (TPTF) against COPD was demonstrated by in vivo and in vitro experiments. The targets and pathways of TPTF for COPD were predicted using network pharmacology and confirmed preliminarily by molecular docking techniques. The critical targets and pathways of TPTF against COPD were validated by Western blot and SPR. The active ingredients of TPTF were selected and identified through SPR. RESULTS: The main active ingredients of TP are flavonoids, which are evaluated through serum chemical composition analysis. TPTF has been demonstrated to be effective in inhibiting inflammation and mucus hypersecretion in both in vivo and in vitro models of COPD. The targets of TPTF against COPD are focused on the EGFR/PI3K/AKT signaling pathway according to Network pharmacology, and the prediction was subsequently validated in the COPD mice. The flavonoids of TP that specifically target on EGFR include Luteolin-7-O-β-d-glucoside, Quercetin-3-O-β-rutinoside, and Apigenin-7-O-glucoside. CONCLUSION: This study demonstrates significant progress in understanding how the pharmacodynamic basis and mechanisms of TP improve COPD. The pharmacodynamic ingredients were identified as TPTF through predictions of serum chemical composition, experimental validation, and identification of SPR. The pharmacodynamic mechanisms were also derived from a comprehensive approach that combined network pharmacology, molecular docking predictions, experimental validation, and SPR identification. The innovative integration of different strategies has led to new findings that flavonoid glycosides, such as Luteolin-7-O-β-d-glucoside, Quercetin-3-O-β-rutinoside, and Apigenin-7-O-glucoside in TPTF, enhance the improvement of COPD by reducing inflammation and mucus hypersecretion associated with the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathways.