Epigenetic alterations in our genetic material can lead to heritable changes in the risk, clinical manifestations, course, and outcomes of many diseases. Understanding these epigenetic mechanisms can help in identifying potential therapeutic targets. This is especially important in necrotizing enterocolitis (NEC), where prenatal as well as postnatal factors impact susceptibility to this devastating condition, but our therapeutic options are limited. Developmental factors affecting intestinal structure and function, our immune system, gut microbiome, and postnatal enteral nutrition are all thought to play a prominent role in this disease. In this manuscript, we have reviewed the epigenetic mechanisms involved in NEC. These include key developmental changes in DNA methylation in the immature intestine, the role of long non-coding RNA (lncRNA) in maintaining intestinal barrier function, epigenetic influences of prenatal inflammation on immunological pathways in NEC pathogenesis such as Toll-Like Receptor 4 (TLR4) and epigenetic changes associated with enteral feeding causing upregulation of pro-inflammatory genes. We have assimilated research findings from our own laboratory with an extensive review of the literature utilizing key terms in multiple databases, including PubMed, EMBASE, and Science Direct.