Abstract: Background and Objective: Acetaminophen (APAP)-induced hepatotoxicity is a severe public health problem in western countries. Current treatment methods for poisoning are limited and novel therapeutic strategies are needed. The aim of the present study was to investigate the protective effect of ginsenosides from the fruits of Panax ginseng (GFG)against APAP-induced liver injury in mice and its potential molecular mechanisms of action. Materials and Methods: In this study, mice were orally administered with 150 or 300 mg kg–1 of GFG for 7 consecutive days, followed by a single injection of APAP (250 mg kg–1). Severe liver injury was observed after 24 h APAP injection and the protective effect of GFG was assessed. Results: The results showed that pre-treatment with GFG reduced the levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Moreover, GFG showed anti-oxidant activities characterized by reducing hepatic MDA contents and increasing hepatic SOD and GSH levels, accompanied by inhibiting expression level of 4-HNE. Likewise, GFG decreased APAP-induced the expression of cytochrome P450 E1 (CYP2E1). Pre-treatment with GFG significantly inhibited pro-inflammatory factors tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), Bax, Bcl-2 and cyclooxygenase-2 (COX-2) levels expression of which contributed to ameliorating APAP caused hepatotoxicity. Furthermore, liver histopathological observation provided further evidence that GFG pretreatment significantly inhibited APAP-induced hepatocyte necrosis, inflammatory cell infiltration. Conclusion: The present study clearly showed that GFG exerted a protective effect against APAP-induced hepatotoxicity due to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.