A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (M pro ) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with M pro , 17 were chosen for evaluation in a kinetic assay for M pro inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC 50 values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1', and P2 pockets of M pro . Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.