Naturally existing -α -glucosidase inhibitors from traditional herbal medicines have attracted considerable interest to treat type 2 diabetes mellitus (T2DM). Hundreds of herbs have been reported to have the potential to inhibit -α -glucosidase. However, most common methods to examine the inhibitors of -α -glucosidase are usually time-consuming. In the current study, the screening of -α -glucosidase ligands from Coptis chinensis Franch extract was undertaken by ultrafiltration liquid chromatography coupled to electrospray ionization tandem mass spectrometry (ultrafiltration LC-ESI-MS(n)). Resultantly, the enzyme inhibition studies showed that Coptis chinensis Franch extract carries the strongest -α -glucosidase inhibitory activity among the five kinds of Chinese herbal extracts. Subsequently, five compounds that could bind to -α -glucosidase in the Coptis chinensis Franch extract were found using ultrafiltration liquid chromatography, and their structures were identified by ESI-MS(n) to be coptisine, epiberberine, jatrorrhizine, berberine, palmatine. Cumulatively, these results were anticipated to be encouraging for applying the Coptis chinensis Franch extracts as efficient anti-diabetic drug candidates.