Ivermectin (IVM) is an FDA-approved drug that has shown antiviral activity against a wide variety of viruses in recent years. IVM inhibits the formation of the importin-α/β1 heterodimeric complex responsible for the translocation and replication of various viral species proteins. Also, IVM hampers SARS-CoV-2 replication in vitro; however, the molecular mechanism through which IVM inhibits SARS-CoV-2 is not well understood. Previous studies have explored the molecular mechanism through which IVM inhibits importin-α and several potential targets associated with COVID-19 by using docking approaches and MD simulations to corroborate the docked complexes. This study explores the energetic and structural properties through which IVM inhibits importin-α and five targets associated with COVID-19 by using docking and MD simulations combined with the molecular mechanics generalized Born surface area (MMGBSA) approach. Energetic and structural analysis showed that the main protease 3CLpro reached the most favorable affinity, followed by importin-α and Nsp9, which shared a similar relationship. Therefore, in vitro activity of IVM can be explained by acting as an inhibitor of importin-α, dimeric 3CLpro, and Nsp9, but mainly over dimeric 3CLpro.Communicated by Ramaswamy H. Sarma.