Chlorogenic acid (CGA), a kind of polyphenol found in coffee, fruits and vegetables, has potent anti-oxidant and anti-inflammatory properties. Our previous studies showed CGA could efficiently alleviate liver fibrosis in rats. However, whether CGA regulates nuclear factor erythroid-2-related factor 2 (Nrf2) anti-oxidant pathway and NLRP3 inflammasome activation and protects against carbon tetrachloride (CCl4)-induced acute liver injury are unknown. We found that CGA could increase Nrf2 activation and expression of Nrf2-related anti-oxidant genes, including HO-1, NQO1 and GCLC. Pretreatment with CGA could reduce CCl4-induced elevation of serum transaminases and alleviate liver pathological abnormalities. CGA also reversed CCl4-induced increase in MDA level and decrease in the levels of GSH, SOD and CAT in liver tissues. Meanwhile, CGA inhibited NLRP3 inflammasome activation, as indicated by the reduced protein expression of NLRP3, Pro-Caspase-1, Caspase-1, Pro-IL-1β and IL-1β. Moreover, CGA reduced serum levels and liver mRNA expression of TNF-α, IL-6 and IL-1β. These results demonstrate that CGA protects against CCl4-induced acute liver injury probably through enhancing Nrf2-mediated anti-oxidant pathway and inhibiting NLRP3 inflammasome activation.