SARS-CoV-2 main protease (M pro ) plays an essential role in proteolysis cleavage that promotes coronavirus replication. Thus, attenuating the activity of this enzyme represents a strategy to develop antiviral agents. We report inhibitory effects against M pro of 40 synthetic chalcones, and cytotoxicity activities, hemolysis, and in silico interactions of active compounds. Seven of them bearing a (E)-3-(furan-2-yl)-1-arylprop-2-en-1-one skeleton (10, 28, and 35-39) showed enzyme inhibition with IC 50 ranging from 13.76 and 36.13 μM. Except for 35 and 36, other active compounds were not cytotoxic up to 150 μM against THP-1 and Vero cell lines. Compounds 10, and 35-39 showed no hemolysis while 28 was weakly hemotoxic at 150 μM. Moreover, molecular docking showed interactions between compound 10 and M pro (PDBID 5RG2 and 5RG3) with proximity to cys145 and His41, suggesting a covalent binding. Products of the reaction between chalcones and cyclohexanethiol indicated that this binding could be a Michael addition type.