ABSTRACT Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long‐lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long‐term programming of metabolic disease. We used a well‐characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up‐regulation of monoacylglycerol O‐acyltransferase (Mogat)1 conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1 expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long‐lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late‐onset insulin resistance and fatty liver disease.—Ramon‐Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez‐Wienese, R., Vilà, M., Palacios‐Marin, I., Fernández‐Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez‐Chillaron, J. C. Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long‐term hepatic steatosis and insulin resistance. FASEB J. 32, 6025–6037 (2018). www.fasebj.org