Postmenopausal osteoporosis caused by estrogen deficiency affects millions of women worldwide. By influencing both osteoblast and osteoclast development, NOD-like receptor thermoprotein structural domain-associated protein 3 (NLRP3) is a key player in the etiology of osteoporosis (OP). The purpose of this research was to look into the mechanism of action of NLRP3 in osteoporosis caused by a lack of estrogen, highlighting that NLRP3 induces osteoblast pyroptosis and thus inflammatory responses in de-ovulated mice, thereby inhibiting osteogenic differentiation and participating in the development of osteoporosis. In de-ovulated mice, we found an enhanced inflammatory response and suppression of osteogenic activity. In vitro experiments, we found a significant increase in markers of cell pyroptosis and inflammatory responses and a significant decrease in markers of osteogenic differentiation in osteoblasts from de-ovulated mice. However, knockdown of the NLRP3 gene inhibited this cell pyroptosis and improved osteogenic differentiation of osteoblasts. Our findings indicate a potential therapeutic potential for the treatment of estrogen deficiency-induced osteoporosis by demonstrating the critical role that NLRP3 inflammatory vesicles and their downstream-mediated cellular pyroptosis play in bone differentiation.