Early life diet programs offspring such that discrepancy between intrauterine and postnatal nutrition will have negative consequences later in life. Specifically, exposure to high‐fat diet (HF) at critical developmental stages is potentially associated with metabolic syndromes; however, it is unclear which epigenetic mechanisms are responsible for such outcomes. We hypothesize that due to differences in DNA methylation, a mismatched perinatal diet and post‐weaning diet is more metabolically detrimental than a lifelong HF diet. In the present experiment, male Sprague‐Dawley rats were exposed to HF diet during gestation and lactation. At weaning, half the animals were kept on the HF diet (HF/HF) and half were switched to a control AIN‐93G diet (HF/C). Complementary Methylated DNA Immunoprecipitation coupled with high‐throughput sequencing (MeDIP‐seq) and Methylation‐sensitive Restriction Enzyme digestion followed by sequencing (MRE‐seq) were used to quantify DNA methylation in the liver. We identified 3,966 differentially methylated regions (DMRs) between HF/C and HF/HF groups. Of these DMRs, 35% were mapped to gene bodies while 6% fell within promoter or downstream regions. Of the differentially methylated genes, 21 were clustered in the type II diabetes mellitus and the adipocytokine signaling pathways, two metabolically relevant systems that are known to respond to HF intake and lead to insulin resistance. Quantitative PCR showed altered expression of many genes in these pathways, including carnitine palmitoyltransferase 1A (Cpt1a), tumor necrosis factor receptor (Tnfrsf1b), retinoid X receptor (Rxra and Rxrb), and acetyl‐CoA carboxylase (Acacb). The remaining 59% of DMRs were not associated with protein coding genes. Sixteen of these DMRs were mapped to non‐coding RNAs including 9 miRNAs, 9 snRNAs, 6 snoRNAs, 1 telomerase, and 1 RNase P. Interestingly, several genes in the type II diabetes mellitus and the adipocytokine signaling pathways were predicted targets of these differentially methylated miRNAs. Our results indicate that compared to a lifelong HF diet, exposure to mismatched early and late life diets induces DNA methylation that impairs insulin‐ and lipid‐related pathways. Furthermore, methylation and expression of miRNA may provide an additional level of epigenetic regulation that drives these metabolic outcomes.Support or Funding InformationUIUC Research Board grant #12192; Data Purchase Program from University of Illinois Library