Sesame oil is a component of traditional health food; it is a natural product with antiinflammatory property. Nonalcoholic steatohepatitis (NASH) is a condition categorized by concurrent fat accumulation and inflammation in liver. NASH is associated with increased liver-related mortality. Disorders in hepatic lipid homeostasis elicit oxidative stress and inflammation, leading to the progression of NASH. A possible hepatoprotective effect of sesame oil on methionine-choline deficient (MCD) diet-induced NASH in C57BL/6 J mice has never been studied. Mice were fed with MCD diet for 28 days to induce NASH. Single doses of sesame oil (1, 2, and 4 mL/kg) were given on 27th day. Aspartate transaminase, alanine transaminase, steatosis, triglycerides, peroxisome proliferator-activated receptor-\(\alpha\), nitric oxide, malondialdehyde, tumor necrosis factor-\(\alpha\), and interlukin-6 were assessed after 28 days. All tested parameters were higher in MCD-treated mice than in normal control mice. In MCD plus sesame oil-treated mice, all tested parameters were significantly attenuated compared with MCD-treated mice. We conclude that a single dose of sesame oil protects against steatohepatitic injury by decreasing oxidative stress and inflammatory cytokines, but increasing peroxisome proliferator-activated receptor-\(\alpha\) expression.