The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging. Display omitted ► Locus-specific alterations of the DNA methylome accompany HSC aging ► Methylation changes target genes expressed downstream of HSCs to alter HSC potential ► HSC potential, DNA methylation, and replicative limits depend on divisional history ► Aging and forced proliferation of HSC results in DNA hypermethylation of PRC2 targets Functional decline of hematopoietic stem cells during aging is linked to proliferation-dependent changes in DNA methylation.