Genipin, as the most effective ingredient of various traditional medications, encompasses antioxidative, anti-inflammatory, and antibacterial capacities. More recently, it is suggested that genipin protects against septic liver damage by restoring autophagy. The purpose of the current study was to explore the protective effect of genipin against carbon tetrachloride- (CCl₄-) induced acute liver injury (ALI) and its underlying molecular machinery. Our results indicated that treatment with genipin significantly reduced CCl₄-induced hepatotoxicity by ameliorating histological liver changes, decreasing the aspartate aminotransferase and alanine transaminase levels, alleviating the secretion of inflammatory cytokines, and promoting autophagic flux. Moreover, genipin effectively induced the conversion of LC3 and inhibition of p62 accumulation. The liver expressions of ATG5, ATG7, and ATG12 were significantly increased by genipin pretreatment in the ALI mice model. This protective effect may be mediated by the inhibition of mTOR and the activation of p38 MAPK signaling pathways. Meanwhile, genipin attenuated CCl₄-induced inflammatory response by inhibiting the NF-κB and STAT3 signaling pathway. In addition, pretreatment with autophagy inhibitor 3-methyladenine (3-MA) or inhibition of p38 MAPK by SB203580 abolished the hepatoprotective effect of genipin. Taken together, our study implicates that genipin has a protective potential against CCl₄-induced hepatotoxicity, which might be strongly associated with the induction of autophagy and the attenuation of inflammatory response.