Nonalcoholic steatohepatitis (NASH) is a highly prevalent liver disease in the world. About 15% to 25% of patients with NASH may progress to cirrhosis and hepatocellular carcinoma. However, there remains no U.S. Food and Drug Administration (FDA)-approved therapy for NASH. Our previous studies indicate that the combination of leucine and metformin or leucine and icariin, a phosphodiesterase type 5 inhibitor (PDE5i), improved nonalcoholic fatty liver disease (NAFLD) in Diet-induced Obesity (DIO) mice. Here we aim to evaluate the synergistic effect of leucine, metformin and sildenafil combination (Leu-Met-Sil) on NASH in Atherosclerosis diet-induced mouse model. Our data show that the Leu-Met-Sil combination significantly suppressed hepatic steatosis and fibrosis. This was associated with reduced alanine aminotransferase (ALT) levels in circulation. The Leu-Met-Sil combination also decreased inflammation and increased fatty acid oxidation in liver, which may contribute to the beneficial effects of the treatment on the NASH phenotype. We conclude that Leu-Met-Sil combination could be a novel therapy for the treatment of NASH.