Estrogen deficiency-related osteoporosis is a skeletal system disorder that affects women after menopause taking a toll on financial and health institutions. Gingival Mesenchymal Stem cells (GMSCs) are a distinctive population of dental tissue-derived stem cells that possess uniquely high proliferation abilities and are capable of self-maintenance and multipotent differentiation. Their use has been investigated in different disease model applications, including cutaneous wound healing models, colitis, and allergy-related inflammatory disease models, but their effect on the bone phenotype of ovariectomy-induced osteoporosis hasn’t been explored. In our study, we show that a single systemic infusion of GMSCs elevated the bone mass reduction caused by Ovariectomy (OVX)-induced osteoporosis in both the femurs and mandibles of OVX mice, they also successfully rescued the function of the defective endogenous population of Bone Marrow Mesenchymal Stem Cells (BMMSCs). We saw that the systemic infusion of GMSCs exerted an immunomodulatory effect on the host, leading to the elevation of T-regulatory lymphocytes (T-regs) and the downregulation of T helper type 1 lymphocytes (Th1) levels in recipient OVX mice. Mechanistically, PD-1/PD-L1 is a popular cellular death pathway being heavily investigated in multiple research fields, In our study, we found that GMSC expresses PD-L1 and that the improved bone phenotype resulting from the GMSC infusion was via the programmed cell death (PD-1/PD-L1) pathway triggering activated T-cell apoptosis in the OVX mice, eventually resulting in an improvement of the bone phenotype.