BACKGROUND/OBJECTIVES: Atherosclerosis is a chronic inflammatory disease developing and progressing in the presence of risk factors including hyperlipidemia, hypercholesterolemia, and chronic inflammation, among others. Atherosclerosis commonly precipitates as ischemic events, transient ischemic attacks, and myocardial infarction. Saturated fatty acids are risk factors; however, their association with epigenetics in the pathophysiology of atherosclerosis is not clearly understood. The preclinical and clinical trials associating atherosclerosis with epigenetics are scarcely documented, and most of the studies reported the use of drugs inhibiting methylation and histone modification to improve atherosclerosis. This narrative review aims to discuss various aspects and the association between a high-fat diet, epigenetic reprogramming, and atherosclerosis. METHODS: A literature search with the keywords high-fat diet, epigenetics, and atherosclerosis, alone or in combination, was conducted to search for articles in the English language. Duplicate articles were removed, and articles related to the subject of this review article were included in this review. RESULTS: A review of the literature suggests that a high-fat diet with saturated fatty acids is a risk factor for atherosclerosis, but this association is multifactorial, and epigenetics play a critical role. However, the connecting link and the underlying molecular and cellular mechanisms are not clearly understood yet and warrant more research. CONCLUSIONS: A high-fat diet rich in saturated fatty acids is a risk factor for atherosclerosis involving epigenetic reprogramming and altered gene expression. The existing preclinical and clinical trials support the role of epigenetics and reversing it using drugs to attenuate atherosclerosis, but definitive evidence warrants larger clinical trials. Further, a high-fat diet in pregnant mothers can manifest as cardiovascular disease in offspring; caution must be taken in pregnant mothers for their diet and nutrients.