Osteoporosis (OP) is a multifactorial metabolic bone disorder commonly observed in the elderly, particularly prevalent in postmenopausal women. However, many conventional anti-osteoporosis drugs have undesirable side effects, limiting their long-term use. Here, we demonstrated that exosomes derived from both young and old healthy human plasma, which exhibited similar morphology, could significantly enhance the proliferation and migration of mesenchymal stem cells (MSCs). Furthermore, treatment with these exosomes increased alkaline phosphatase (ALP) activity, enhanced the mineralization of MSCs, and decreased the number of osteoclasts in vitro. When intravenously injected into rats, these exosomes accumulated in bone tissue. In vivo experiments demonstrated that both types of exosomes had a beneficial effect on osteoporosis by facilitating bone formation and suppressing osteoclast differentiation in an ovariectomized (OVX)-induced osteoporotic rat model. Strikingly, exosomes derived from young healthy human plasma exhibited stronger anti-osteoporosis effect. The miRNA sequencing analysis showed that miR-142-5p expression was significantly higher in the exosomes from young healthy adult plasma compared to in exosomes from older controls. Importantly, miR-142-5p overexpression exerted similar pro-osteogenic effects to those of exosomes from young healthy human plasma, while miR-142-5p downregulation had the opposite effect on osteogenic differentiation of MSCs. The anti-osteoporosis effect of exosomes from young healthy adult plasma were reversed upon miR-142-5p inhibition. In addition, ZFPM2 was a potential target of miR-142-5p involved in osteoporosis. Therefore, our study reveals the potential anti-osteoporosis effects of plasma exosomes and their underlying mechanisms, thereby providing an effective therapeutic strategy for clinical treatment of osteoporosis.© 2025 The Authors.