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Penthorum chinense Pursh (PCP) is a popular traditional medicinal plant in China, widely used for the treatment of a variety of liver diseases. Although it has been long recognized that the main active elements of PCP are contained in ethyl acetate fraction (EAF), little is known so far in terms of the relative effectiveness of EAF derived from the stems versus leaves of this plant. In the current study, we prepared EAF by reflux extraction and sequential extraction from the stems (SEAF) and leaves (LEAF) of PCP and tested their hepatoprotective efficacies. The extract rates and flavonoid contents of LEAF were higher than those of SEAF. EAFs (>50 μg·mL−1) prevented lipid accumulation in cells and protected against lipotoxicity injury when the concentration exceeded 25 μg·mL−1. More than 95% free radicals released by 2,2-diphenyl-1-picrylhydrazyl (DPPH) were eliminated by 25 μg·mL−1 SEAF and 50 μg·mL−1 LEAF, respectively. Further, EAFs (25 μg·mL−1) also showed protective antioxidant effects, with the activity of LEAF being significantly higher than that of SEAF. EAFs (10 mg·mL−1) also showed similar unspecific bacteriostatic activity. In comparison with SEAF, LEAF contained more flavonoids and had a higher anti-oxidation capability and for these reasons we suggest it should be better for clinical use.