Enzyme inhibitors working by -acylation of nucleophilic serine residues are of immense medicinal importance, as exemplified by the β-lactam antibiotics. By contrast, inhibition of nucleophilic cysteine enzymes by -acylation has not been widely exploited for medicinal applications. The SARS-CoV-2 main protease (M ) is a nucleophilic cysteine protease and a validated therapeutic target for COVID-19 treatment using small-molecule inhibitors. The clinically used M inhibitors nirmatrelvir and simnotrelvir work reversible covalent reaction of their electrophilic nitrile with the M nucleophilic cysteine (Cys145). We report combined structure activity relationship and mass spectrometric studies revealing that appropriately functionalized γ-lactams can potently inhibit M by reversible covalent reaction with Cys145 of M . The results suggest that γ-lactams have potential as electrophilic warheads for development of covalently reacting small-molecule inhibitors of M and, by implication, other nucleophilic cysteine enzymes.