The aim of the present study was to evaluate the effects of Penthorum chinense Pursh (PCP), a health food and folk medicine, against acute alcohol-induced liver injury and further to elucidate its probable mechanisms. Male C57BL/6 mice were treated with an aqueous extract of PCP (5.2 and 10.3 g per kg BW) once daily for 7 consecutive days prior to ethanol gavage (4.7 g kg^-1) every 12 h for a total of three doses. Pretreatment with PCP significantly decreased the elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic triglyceride after the last ethanol administration. PCP suppressed the elevation of the malondialdehyde (MDA) level, restored the glutathione (GSH) level and enhanced the activities of superoxide dismutase (SOD) and catalase (CAT) in both the serum and liver, which were associated with the inhibition of hepatic cytochrome P450 2E1 (CYP2E1). In addition, alcohol exposure markedly induced the lipolysis of white adipose tissue (WAT) through up-regulating protein expressions of adipose triglyceride lipase (ATGL) and phosphorylation of hormone-sensitive lipase (p-HSL), and enhancing the fatty acid uptake capacity in the liver by elevated hepatic CD36 expression, which were attenuated by PCP treatment. These data demonstrated that pre-treatment with PCP protected against acute ethanol-induced liver injury, possibly by reducing CYP2E1-dependent oxidative stress and ameliorating dysfunctional WAT derived-fatty acid influx to the liver. Our findings suggest that PCP might be a promising agent for the prevention of acute alcohol-induced liver injury.