 This study evaluates the potential mechanisms of salimerin as an antiviral agent against SARS-CoV-2 infection using multiple disciplinary approaches and methodologies, including molecular docking, network pharmacology, bioinformatic methods, gene function analysis, and drug target screening. Salimerin compounds, such as Cilibin A, B and Saliminin, displayed triplicate functions against SARS-CoV-2 infection, including directly binding with human angiotensin converting enzyme 2, ACE2, to inhibit SARS-CoV-2 entry into the host cells, directly binding with viral proteins RDRP and helicase to inhibit viral replication and proliferation, and regulating host immune response to indirectly inhibit viral infection. The targets of salimerin molecules in immune regulation were screened out, such as pro-inflammatory cytokines TNF and IL-6 and cell growth factors VEGF and EGF. The molecular mechanism of drug target protein interaction was investigated, including the binding pockets of drug molecules in human ACE2 and viral proteins, the formation of hydrogen bonds, hydrophobic interactions, and other drug protein ligand interactions. Finally, the drug-likeness results of candidate molecules passed the criteria for drug screening. This article was authored by Chun Aizhang, Yuxiang Sway, Shui Lu, and others. We are article.tv, links in the description below.