Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, and it can proceed to cirrhosis and hepatocellular carcinoma, as well as cardiovascular disease, chronic renal disease, and other complications, resulting in a massive economic burden. At the moment, nicotinamide adenine dinucleotide (NAD+) is thought to be a possible treatment target for NAFLD, besides Cluster of differentiation (CD38) is the primary NAD+ degrading enzyme in mammals and may play a role in the pathophysiology of NAFLD. For example, CD38 regulates Sirtuin 1 activity and hence affects inflammatory responses. CD38 inhibitors enhance glucose intolerance and insulin resistance in mice and lipid accumulation in the liver is greatly decreased in CD38-deficient mice...Ablation of SIRT3 in CD38-deficient mice eliminates the protective role of CD38 inhibition in HFD-induced obesity .Thus, the role of CD38 as a regulator of obesity and energy expenditure may also be related to thermogenesis and mediated by a NAD+-SIRT-dependent mechanism...This review describes the role of CD38 in the development of NAFLD in terms of Macrophage-1, insulin resistance, and abnormal lipid accumulation in order to offer recommendations for future NAFLD pharmacological trials.