Over the last few years, consistent data have demonstrated that creatine (Cr) supplementation prevents the accumulation of fat in rat liver as well as the progression of fatty liver disease in different situations. Studies have demonstrated that Cr is effective and prevents fatty liver in high-fat and choline-deficient diets and in hepatoma cells in vitro. Because Cr synthesis is responsible for a considerable consumption of hepatic methyl groups, studies have tested the idea that Cr supplementation could modulate phospholipid formation and VLDL secretion. Studies have also demonstrated Cr is able to modulate the expression of key genes related to fatty acid oxidation in hepatocyte cell culture and in rat liver. However, to date, the mechanism by which Cr exerts protective effects against fatty liver is poorly understood. Therefore, the present review aims to summarize the studies involving the therapeutic use of Cr supplementation on fatty liver disease and to explore the mechanisms involved in one-carbon and fatty acid metabolism for the preventive effects of Cr supplementation on fat liver accumulation. Although a small number of studies have been conducted to date, we consider Cr as a new and promising therapeutic strategy to control fat accumulation in the liver as well as the progression of fatty liver disease.