Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic . Here, we screened by high-throughput docking 6,000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3CL main protease, a chymotrypsin-like enzyme that is essential for viral replication . For 19 candidate hits, parallel in vitro fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed . One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3CL main protease inhibitor in vitro (IC50 value of 29 μM) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells . Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3CL main protease inhibitor in vitro, but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication in Vero-CCL81 cells . Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs . Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry . Our study shows that combining computational and cellular screening is an efficient means to identify existing drugs with repurposing potential as antiviral compounds . Future studies should aim at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option . IMPORTANCE Successful repurposing of existing drugs as COVID-19 therapeutics would be a rapid and important means to limit disease severity during the SARS-CoV-2 pandemic . In this study, we used a computational screening approach to identify existing drugs that might inhibit the function of a critical enzyme (the 3CL main protease) encoded by the causative agent of COVID-19, SARS-CoV-2 . While we found that diclazuril (an investigational human drug already approved for use in animals) inhibited this viral enzyme in vitro, it only showed modest ability to inhibit SARS-CoV-2 replication in cells . However, our approach serendipitously identified lenvatinib (an anti-cancer drug approved for use in humans) as a potent inhibitor of SARS-CoV-2 replication when combined with the existing approved antiviral drug, remdesivir . Our findings raise the possibility that future studies to understand the molecular mechanisms underlying the lenvatinib/remdesivir synergy could uncover new therapeutic principles for treatment of COVID-19 or similar viral diseases.