An efficient method combined with fingerprint and chemometric analyses was developed to evaluate the quality of the traditional Chinese medicine plant Penthorum chinense Pursh. Nine samples were collected from different regions during different harvest periods, and 17 components in the form of extracts were simultaneously examined to assess quality by using high-performance liquid chromatography. The hepatoprotective effects of components were investigated by assessing the inhibition of SMMC-7721 cell growth. The results indicated that the quality control method was accurate, stable, and reliable, and the hierarchical heat-map cluster and the principle component analyses confirmed that the classification of all nine samples was consistent. Quercetin and ellagitannins including pinocembrin-7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-glucose (PGHG), thonningianin A, thonningianin B, and other flavonoids were abundant in the extracts, and significantly contributed to the hepatoprotective effects.