The main proteases (M ^pro) are highly conserved cysteine-rich proteins that can be covalently modified by numerous natural and synthetic compounds. Herein, we constructed an integrative approach to efficiently discover covalent inhibitors of M ^pro from complex herbal matrices. This work begins with biological screening of sixty clinically used antiviral herbal medicines, among which Lonicera japonica (LJ) demonstrated the strongest anti-M ^pro effect (IC ₅₀ = 37.82 μg/mL). Mass spectrometry-based chemical analysis and chemoproteomic profiling revealed that LJ extract contains at least 50 constituents, of which 22 exhibited the capability to covalently modify M ^pro. We subsequently verified the anti-M ^pro effects of these covalent binders. Gallic acid and quercetin were found to potently inhibit SARS-CoV-2 M ^pro in dose- and time- dependent manners, with the IC ₅₀ values below 10 µM. The inactivation kinetics, binding affinity and binding mode of gallic acid and quercetin were further characterized by fluorescence resonance energy transfer, surface plasmon resonance, and covalent docking simulations. Overall, this study established a practical approach for efficiently discovering the covalent inhibitors of M ^pro from herbal medicines by integrating target-based high-throughput screening and mass spectrometry-based assays, which would greatly facilitate the discovery of key anti-viral constituents from medicinal plants.