ABSTRACTAging is a major risk factor for most chronic diseases, including osteoporosis, and is characterized by an accumulation of senescent cells in various tissues. MicroRNAs (miRNAs) are critical regulators of bone aging and cellular senescence. Here, we report thatmiR‐19a‐3pdecreases with age in bone samples from mice as well as in posterior iliac crest bone biopsies of younger versus older healthy women.miR‐19a‐3palso decreased in mouse bone marrow stromal cells following induction of senescence using etoposide, H2O2, or serial passaging. To explore the transcriptomic effects ofmiR‐19a‐3p, we performed RNA sequencing of mouse calvarial osteoblasts transfected with control ormiR‐19a‐3pmimics and found thatmiR‐19a‐3poverexpression significantly altered the expression of various senescence, senescence‐associated secretory phenotype‐related, and proliferation genes. Specifically,miR‐19a‐3poverexpression in nonsenescent osteoblasts significantly suppressedp16Ink4aandp21Cip1gene expression and increased their proliferative capacity. Finally, we established a novel senotherapeutic role for this miRNA by treatingmiR‐19a‐3pexpressing cells with H2O2to induce senescence. Interestingly, these cells exhibited lowerp16Ink4aandp21Cip1expression, increased proliferation‐related gene expression, and reduced SA‐β‐Gal+ cells. Our results thus establish thatmiR‐19a‐3pis a senescence‐associated miRNA that decreases with age in mouse and human bones and is a potential senotherapeutic target for age‐related bone loss. © 2023 The Authors.JBMR Pluspublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.