Methionine is an essential amino acid that plays important roles in mammalian metabolism. Interestingly, previous studies have consistently shown that a methionine-restricted diet (MRD) reduces hepatic lipid levels, reactive oxygen species production, and oxidative stress damage. However, the mechanisms responsible for these beneficial effects are unknown. Therefore, our study was aimed at investigating the hepatic systemic metabolic responses to MRD in high-fat-diet (HFD) mice and to clarify the possible mechanisms of such responses. C57BL/6J mice were fed a control diet (0.86% methionine + 4% fat), HFD (0.86% methionine + 20% fat), or MRD (0.17% methionine + 20% fat) for 22 consecutive weeks, and euthanized at week 11 or week 22. Our results showed that HFD inhibited hepatic energy expenditure, induced steatosis and oxidative stress, and decreased hydrogen sulfide (H2S) production in the mouse liver. MRD reduced the body weight, liver fat percentage, and plasma and hepatic lipid profiles. Moreover, MRD decreased lipid synthesis, increased energy metabolism (e.g. lipid catabolism and fatty acid oxidation, glycolysis and tricarboxylic acid cycle metabolism, and amino acid catabolism), enhanced the activity of antioxidant enzymes, and reduced the levels of oxidative damage products and purine metabolism in the liver. Furthermore, MRD up-regulated the hepatic gene and protein expression of cystathionine-γ-lyase (CSE), elevated the hepatic CSE activity, and promoted hepatic H2S production. These findings suggest that MRD can ameliorate the hepatic metabolic disorders induced by HFD and especially reduce hepatic steatosis and oxidative stress likely through increasing hepatic H2S production.