gamma-Mangostin (gamma-man), an active compound from Garcinia mangostana L., has been discovered as a hepatoprotective agent against oxidative injury. However, the underlying mechanisms remained unclear. The current study showed that gamma-man stimulated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) to enhance antioxidant capacity under oxidative stress, which was partially reversed by treatment of the NRF2 inhibitor, all-trans-retinoic acid. Moreover, gamma-man increased the expression and activity of SIRT1 (silent mating type information regulation 2 homolog 1), which facilitated the deacetylation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha to improve the mitochondrial function in L02 cells. The protective effect of gamma-man was partially blocked by treatment of the SIRT1 inhibitor tenovin-1 or SIRT1 knockdown. In vivo studies showed gamma-man protected mice from carbon tetrachloride-induced acute liver injury, through up-regulation of NRF2 and SIRT1. Thus, gamma-man might be a candidate to protect liver from acute oxidative injury.