Hematopoietic stem cells (HSCs) are immature cells that can develop into all types of blood cells, making them critical regulators of blood composition. However, during aging, HSCs undergo a process called senescence, in which their functionality starts to fade, leading to issues like reduced immune cell populations or leukemia. HSC senescence is influenced by various age-related factors, like accumulated DNA damage or epigenetic (non-DNA-altering) changes in gene expression, and it’s regulated by small RNA molecules known as microRNAs (miRNAs). For example, the miR-212/132 cluster binds to the FOXO3 gene to affect HSC life cycles, function, and survival and is upregulated with aging, while miR-125b, which can help HSCs resist stress and cell death, is downregulated in aging HSCs. In the context of aging-related disease, a lack of miR-13/145 affects HSC activity via the TGFβ/DAB2 pathway, increasing leukemia susceptibility, and miR-146a deficiency enhances HSC senescence and contributes to inflammation in acute myeloid leukemia. Given the roles of miRNAs in HSC regulation, targeting these molecules could be a good strategy to limit HSC senescence, but more research is needed to determine exactly how to leverage miRNA–HSC relationships in order to slow HSC aging and prevent related diseases.