Background: The plant-derived bioflavonoid amentoflavone has many important biological activities, among them remarkable antiviral effects, even against severe acute respiratory syndrome Coronavirus (SARS-CoV). It inhibits severe acute respiratory syndrome coronavirus (SARS-CoV) with an IC50 value of 8.3 μM. TMPRSS-2 activity is now thought to be the only factor necessary for cell entry and viral pathogenesis). In comparison, 3CLPRO is needed for COVID-19 replication and maturation during its life cycle. Aim: This study aims to perform an in silico study on amentoflavone activity against structural and non-structural severe acute respiratory syndrome coronavirus (SARS-CoV)-2 3-chymotrypsin-like protease (3CLPRO) and human transmembrane protease serine 2 (TMPRSS-2) proteins. Materials and Methods: Molecular docking studies were carried out using compounds against 3CLPRO and TMPRSS-2 proteins through the Swiss model, Uniport, PROCHECK, Swiss PDB viewer, PyMol, PyRx, and Desmond (Schrödinger package) computerized software. Results: Amentoflavone showed strong interactions -9.5 and -7.4 kcal/mol with 3CLPRO and TMPRSS2 proteins, respectively. In any case, it had higher binding affinities than currently approved antiviral drugs, which are underutilized in coronavirus disease (COVID-19). Conclusion: Amentoflavone may be one of the potential leads (drug candidate) to fight human coronavirus, including SARS-CoV-2. Further in vivo studies are needed to support the findings of this study.