Background: Huashi Baidu granule (HSBD), an approved herbal formula for treating COVID-19, demonstrates safety and efficacy. Despite its market approval, the detailed methodology and identification of its active components remain unexplored, leaving its bioactive constituents and action mechanisms unclear. Methods: This study investigated the potential mechanisms of HSBD’s active ingredient in treating COVID-19. Our approach integrated various techniques, including the GEO database, network pharmacology, surface plasmon resonance, molecular docking and molecular dynamics simulations, to formulate a comprehensive research strategy. Results: The UHPLC-QqQ-MS/MS method employed for HSBD analysis proved stable, reliable, and reproducible. We identified 25 principal components in HSBD, with seven compounds detected in plasma, namely pogostone, p-hydroxybenzoic acid, Paeoniflorin, Rhein, Emodin, ephedrine hydrochloride, and pseudoephedrine hydrochloride. Protein-Protein Interaction (PPI) network analysis identified MMP9 as a pivotal target, while KEGG pathway analysis indicated that HSBD mediates its therapeutic effects on COVID-19 primarily through the TNF-α and PI3K-AKT pathways. Surface plasmon resonance analysis revealed that Paeoniflorin and Rhein exert their antiviral effects by interacting with RBD and ACE2, respectively. In contrast, Emodin’s antiviral mechanism predominantly involves binding to MMP9. Molecular docking results indicated strong binding affinities of Rhein and Paeoniflorin to the hACE2 protein, and high binding affinities of Paeoniflorin, Rhein, and Emodin to the MMP9 protein, all of which were corroborated by molecular dynamics simulations. Conclusion: We investigated the methodology and identified the active components of HSBD, focusing on those absorbed into the plasma, to elucidate the effective material basis of HSBD in the treatment of COVID-19, our research offer insightful exploration into its mechanisms of action against COVID-19.