Activation of NK cells with IL-12/15/18 generates two cell fates: enriched memory-like (eML) and effector conventional (effcNK) NK cells. Our group demonstrated that eML NK cells are epigenetically distinct from effcNK cells and cNK cells (PMID: 38941480). However, the molecular mechanisms responsible for the distinct chromatin accessibility (ATAC-seq) profile in eML NK cells are not well understood. We therefore examined differences in DNA methylation and histone modifications. Whole genome bisulfite sequencing and analysis of differentially methylated regions (DMRs) of in vitro differentiated sorted conventional (c)NK, effcNK, and eML NK cells revealed a distinct DNA methylation profile in eML NK cells. This was dominated by regions with increased methylation in eML NK cells. These data were consistent with ATAC-seq in which eML NK cells displayed reduced chromatin accessibility, and bulk RNA-seq that showed significantly downregulated genes in eML NK cells. Among the DMRs, the promoter region of ENTPD1 (CD39), and CNS-1 region of IFNG locus were hypomethylated in eML NK cells compared to cNK. To investigate histone modification, we assessed H3K27me3 levels by CUT&TAG expecting to find increased levels of this repressive mark associated with downregulated genes in eML NK cells. While we found 2,181 differential H3K27me3 regions that are significant between cNK and eML NK cells, eML NK cells did not have more H3K27me3 increased regions compared to cNK. Increased H3K27me3 marks were observed at the B3GAT1 (CD57) locus in eML NK cells, matching RNA and protein data. Our study highlights that DNA methylation and H3K27me3 modification partly control the chromatin landscape in eML NK cells and are responsible for some of the transcriptional differences observed between eML NK cells and effcNK or cNK cells. Additional histone modification mechanisms warrant further study in eML NK cells.