Abstract COVID-19, the global pandemic caused by SARS-Corona virus 2 (SARS-CoV-2), recently ravaged the World with various efforts charged towards finding therapeutic drug targets for this novel virus. The identification of COVID-19 main protease (Mpro) opened the possibility of testing new families of inhibitors as potential anti-coronaviral drugs. Protein-drug interaction is of pivotal importance to understanding the structural features essential for any ligand affinity. This study evaluated the efficacy of an isolated bioactive plant compound and synthetic tetraazamacrocycles against COVID-19 Mpro by molecular docking. Molecular docking investigations were performed using PyRx, Auto Dock vina and Discovery Studio (DS) to analyze the inhibition probability of these compounds against COVID-19. COVID-19 Mpro (PDB ID: 6LU7: Resolution 2.16 Å) was docked with 1 flavonoid and 3 tetraaza-macrocyclic compounds comparatively with known anti-viral drugs (Remdesivir (REMD) and Nelfinavir (NELF)) and hydroxychloroquine (HCQ). Docking studies showed H-TEAD, 5 interacting with 5 residues having the highest binding affinity of −9.4 kcal/mol, followed by TEAD with 5 residue interactions and a binding affinity value of −9.4 kcal/mol, HA-TEAD, 7 has 5 interactions with a binding affinity of −9.3 kcal/mol, and Siam1 has 6 interactions with a binding energy of −7.8 kcal/mol. All the docked potential drugs have binding energies higher than the reference drugs HCQ, 1 and REMD, 2 connoting greater activity except NELF, 3 whose value is only lower than the 3 macrocycles (HA-TEAD, 7 and H-TEAD, 5 and TEA1, 6). They are bound through hydrogen bonds, arene-anion and arene-cation interactions. The trend of binding affinity show H-TEAD (−9.4 kcal/mol) = TEAD1 (−9.4 kcal/mol) > HA-TEAD (−9.3 kcal/mol) > NELF (−8.7 kcal/mol) > Siamone (−8.8 kcal/mol) > HCQ (−7.2 kcal/mol) > REMD (−6.2 kcal/mol) while the number of interactions shows REMD > HA-TEAD = HCQ > Siamone > NELF > H-TEAD > TEAD1. This study, hence, validates the activity of HCQ against COVID-19 and provides a foundation for advanced experimental research, to evaluate the real pharmaceutical potentials of these compounds, towards finding a cure for COVID-19 and other related diseases.