Effects of saponins from leaves of Panax notoginseng (LPNS) against alcoholic liver injury were evaluated, and their probable molecular mechanisms were further elucidated in a mouse model of chronic-plus-single-binge ethanol feeding. Alcohol exposure dramatically increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triacylglycerol (TG) and endotoxin; these elevations were attenuated by treatment with LPNS at a dose of 100 or 300 mg/kg. LPNS was also found to suppress thiobarbituric acid reactive substances (TBARS) production, enhance glutathione (GSH) level and superoxide dismutase (SOD) activity in liver. The protective of LPNS against oxidative stress was associated with down-regulation of hepatic cytochrome P450 2E1 (CYP2E1), and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1). Additionally, LPNS ameliorated gut leakiness via upregulating the expressions of tight junction proteins, and suppressed endotoxin-mediated inflammation via down-regulating toll-like receptor-4 (TLR-4), CD14 and p-NF-κB p65. These results demonstrate that treatment with LPNS effectively protects against alcoholic liver injury through reducing ethanol-induced oxidative stress and ameliorating gut-derived endotoxin-mediated inflammation.