Nonalcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of fat in the liver in the absence of any other disease related to liver steatosis, which includes a wide spectrum ranging from mild asymptomatic fatty liver to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, the pathogenesis of NASH has not been established. In this study, we investigated the involvement of the G-protein-coupled receptor 120/free fatty acid receptor 4 (GPR120/FFAR4) in the pathogenesis of NASH. Mice fed a 0.1% methionine- and choline-deficient l-amino acid-defined, high-fat (CDAHF) diet showed a significant increase in plasma aspartate aminotransferase and alanine aminotransferase levels, fatty deposition, inflammatory cell infiltration, and slight fibrosis. Docosahexanoic acid (DHA, a GPR120/FFAR4 agonist) suppressed the inflammatory cytokines in hepatic tissues and prevented liver fibrosis. On the other hand, GPR120/FFAR4-deficient CDAHF-fed mice showed increments in the number of hepatic crown-like structures and immunoreactivity to F4/80-positive cells compared with wild-type mice. Furthermore, the levels of hepatic TNF-α mRNA expression increased in GPR120-deficient mice. These findings suggest that the GPR120/FFAR4-mediating system could be a key signaling pathway to prevent the development of NASH. In this review, we describe our recent data showing that GPR120/FFAR4 could be a therapeutic target in NASH/NAFLD.