The COVID-19 pandemic has spread rapidly and posed an unprecedented threat to the global economy and human health. Broad-spectrum antivirals are currently being administered to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). China’s prevention and treatment guidelines suggest the use of an antiinfluenza drug, arbidol, for the clinical treatment of COVID-19. Reports indicate that arbidol could neutralize SARS-CoV-2. Monotherapy with arbidol is found to be superior to lopinavir-ritonavir or favipiravir for treating COVID-19. In SARS-CoV-2 infection, arbidol acts by interfering with viral binding to the host cells. However, the detailed mechanism through which arbidol induces the inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the mechanism underlying membrane fusion inhibition by arbidol for SARS-CoV-2. Molecular dynamics (MD) simulation-based analyses demonstrate that arbidol binds and stabilizes at the receptor-binding domain (RBD)/ACE2 interface with a high affinity. It forms stronger intermolecular interactions with the RBD than ACE2. Analyses of the detailed decomposition of energy components and binding affinities revealed a substantial increase in the affinity between the RBD and ACE2 in the arbidol-bound RBD/ACE2 complex, suggesting that arbidol could generate favorable interactions between them. Based on our MD simulation results, we propose that the binding of arbidol induces structural rigidity in the viral glycoprotein, resulting in a restriction of the conformational rearrangements associated with membrane fusion and virus entry. Furthermore, key residues of the RBD and ACE2 that interact with arbidol were identified, opening the door for developing therapeutic strategies and higher-efficacy arbidol derivatives or lead drug candidates.Copyright © 2020 Elsevier B.V. All rights reserved.