The 3-chymotrypsin-like protease (3CL) is a crucial enzyme for the replication of coronaviruses, notable for its high conservation across viral species and the lack of human analogs. These characteristics make it a prime target for the development of broad-spectrum antiviral medications. In this work, we incorporated the zolinium as a hydrophilic group and a ketone as the covalent warhead to develop novel agents targeting SARS-CoV-2 3CL. We designed and synthesized 60 derivatives to systematically study their structure-activity relationships (SAR). Of these, compound 46 demonstrated the most potent inhibition against 3CL (IC = 1.75 ± 0.039 μM) and good selectivity against other five enzymes, with reasonable chemical stability and rapid reactivity with cysteine. Mass spectrometry-based peptide mapping revealed that the ketone group of compound 46 covalently modified Cys44 of SARS-CoV-2 3CL. The inactivation kinetics indicated that compound 46 reduced the 3CL activity in a time- and dose-dependent manner, with an inactivation efficiency constant (k/K) of 0.011 min μM. Further covalent docking and molecular dynamics simulations elucidated the binding mechanism involving the disruption of protein's dimer interface and stability, which was partially validated by Native-PAGE analysis. Moreover, compound 46 exhibited negligible cytotoxicity and good metabolic stability in liver microsome assays, positioning it as a promising covalent lead for the advancement of broad-spectrum anti-coronavirus therapies.