Abstract Fulminant hepatic failure (FHF) is a life-threatening clinical syndrome, with liver transplantation being the only effective therapy. Sulforaphane (SFN) is a natural compound that is extracted from cruciferous vegetables and possesses potent anti-inflammatory, antioxidant, and anti-cancer activities. This study was designed to test the hypothesis that SFN (3mg/kg) may protect against FHF induced in rats by administering a combination of D-galactosamine (GalN; 300mg/kg) and lipopolysaccharide (LPS; 30μg/kg). The rats were given a single intraperitoneal injection of SFN, one h before the FHF induction. SFN reduced the mortality and alleviated the pathological liver injury. In addition, SFN significantly reduced the increase in serum aminotransferase activities and lipid peroxidation. The glutathione content decreased in the GalN/LPS group, and this decrease was attenuated by SFN. Increases in serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10, which were observed in GalN/LPS-treated rats, were significantly reduced after using SFN. The GalN/LPS treatment increased the expression of superoxide dismutase-1, glutathione peroxidase 2, catalase, and heme oxygenase-1 genes. SFN inhibited the induction of reactive oxygen species scavenging proteins. Moreover, SFN inhibited GalN/LPS-induced caspase-3 activation and suppressed FAS and FASL expression. These findings suggest that SFN alleviates GalN/LPS-induced liver injury, possibly by exerting antioxidant, anti-inflammatory, and anti-apoptotic effects and modulating certain antioxidant defense enzymes.