Although periprosthetic osteolysis induced by wear debris particles is significantly elevated in senior (65+ years old) patients, most of the published pre-clinical studies were performed using young (less than three-month old) mice indicating the critical need to employ experimental models of particle-induced osteolysis involving mice with advanced age. Emerging evidence indicates that currently available antiresorptive bone therapies have serious age-dependent side effects. However, a resurgence of healthcare interest has occurred in glycyrrhizin (GLY), a natural extract from the licorice roots, as alternative sources of drugs for treating inflammatory bone lytic diseases and prevention of cellular senescence. This study investigated the effects of GLY on inflammatory bone loss as well as expression patterns of senescence-associated secretory phenotype and senescence-protective markers using an experimental calvarium osteolytic model induced in aged (twenty-four-month-old) mice by polymethylmethacrylate (PMMA) particles. Our results indicate that local treatment with GLY significantly diminished the size of inflammatory osteolytic lesions in aged mice via the number of CXCR4+OCPs and Tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts. Furthermore, GLY dramatically decreased the amounts of senescence-associated secretory phenotype markers, including pro-inflammatory macrophage migration inhibitory factor (MIF) chemokine, and cathepsins B and K in the bone lesions of aged mice. By contrast, GLY significantly elevated expression patterns of senescence-protective markers, including homeostatic stromal derived factor-1 (SDF-1) chemokine, and sirtuin-1, and sirtuin-6, in the PMMA particle-induced calvarial lesions of aged mice. Collectively, these data suggest that GLY can be used for the development of novel therapies to control bone loss and tissue aging in senior patients with periprosthetic osteolysis.