The pathophysiology of nonalcoholic steatohepatitis (NASH) is still not fully understood, and available treatments are not entirely satisfactory. Steatosis progression to NASH is associated with deleterious action of reactive oxygen species, mitochondrial dysfunction, and inflammatory cytokines. We investigated the use of curcumin (compared to vitamin E) in the treatment of NASH. Experimental NASH was induced in rabbits by the intake of a high-fat diet. Oxidative stress status, histology, lipid metabolism, and TNF-alpha protein levels were assessed in liver. The high-fat diet induced pathologically assessed NASH, and compared to healthy controls, raised the levels of aminotransferases, reduced mitochondrial antioxidants, increased mitochondrial reactive oxygen species, and led to poor mitochondrial function as well as to higher TNF-alpha protein levels. Curcumin administration together with the high-fat diet led to rabbits with a lower NASH grade and lower levels of aminotransferases, higher values for mitochondrial antioxidants, lower mitochondrial reactive oxygen species, an improved mitochondrial function, and lower levels of TNF-alpha protein levels. Vitamin E treatment was unable to reduce NASH. In conclusion, curcumin might be useful in the management of NASH through a mechanism involving the antioxidant, anti-inflammatory, and mitochondrial-protective potential of curcumin.