The rapid spread of COVID-19 has caused a worldwide public health crisis. For prompt and effective development of antivirals for SARS-CoV-2, the pathogen of COVID-19, drug repurposing has been broadly conducted by targeting the main protease (M), a key enzyme responsible for the replication of virus inside the host. In this study, we evaluate the inhibition potency of a nitrothiazole-containing drug, halicin, and reveal its reaction and interaction mechanism with M. The potency test shows that halicin inhibits the activity of M an IC of 181.7 ​nM. Native mass spectrometry and X-ray crystallography studies clearly indicate that the nitrothiazole fragment of halicin covalently binds to the catalytic cysteine C145 of M. Interaction and conformational changes inside the active site of M suggest a favorable nucleophilic aromatic substitution reaction mechanism between M C145 and halicin, explaining the high inhibition potency of halicin towards M.