To explore the characteristics and molecular mechanism of core combination in “three medicines and three prescriptions” against Coronavirus Disease 2019(COVID-19) based on network pharmacology.Methods:The core combination in “three medicines and three prescriptions” was analyzed for Chinese medicine properties(qi，flavor，and meridian tropism) and toxicity with the aid of the Chinese Pharmacopoeia(2015).The drug efficacies were analyzed and the medication regularity was summarized based on the TCMATCOV platform.The targets of the core combination were predicted by the BATMAN-TCM and COVID-19 targets were obtained from data mining and databases，such as GeneCards，PubChem，DisGeNET，and UniProt.Cytoscape was used to construct a chemical component-core combination-Chinese medicine property and toxicity network.Subsequently，the Venn diagram and protein-protein interaction(PPI) network were employed to screen the candidate targets of the core combination.Then the targets were enriched and analyzed by DAVID，Metascape，and FunRich.Finally，CB-Dock was used for molecular docking calculation and verification of candidate components and key targets.Results:The “three medicines and three prescriptions” contain 48 Chinese medicinal drugs，and most of them are warm，plain，and cold in nature，pungent，sweet，and plain in flavor，and act on lung，stomach，and spleen meridians.Based on the frequency statistics，the core combination in “three medicines and three prescriptions” contains Ephedrae Herba，Pogostemonis Herba，Armeniacae Semen Amarum，Glycyrrhizae Radix et Rhizoma，and Gypsum Fibrosum.As revealed by results，100 chemical components and 449 potential targets of the core combination were obtained，and 77 candidate targets were screened out to act on COVID-19 according to the Venn diagram and PPI network.The enrichment analysis yielded 361 entries of GO biological processes and 120 KEGG pathways.In light of the classification of signaling pathways，the core combination may participate in multiple signaling pathways in the infectious disease system，immune system，nervous system，and endocrine system of the human body to treat COVID-19.Conclusion:The present study explored the Chinese medicine properties(qi，flavor，and meridian tropism)，potential active components，and targets，as well as biological processes and pathways of “three medicines and three prescriptions” for the prevention and treatment of COVID-19 based on the network pharmacology，which is expected to provide references for clinical application of “three medicines and three prescriptions” and further development of new drugs.