Osteoporosis and other forms of inflammatory bone loss are marked by disrupted bone remodelling due to an imbalance between osteoclast-mediated bone resorption and osteoblast-driven bone formation. This imbalance is often exacerbated by chronic inflammation and gut microbiota dysbiosis. Recently, gut-associated metabolites (GAMs), particularly secondary bile acids, such as deoxycholic acid (DCA), have gained attention for their immunomodulatory roles in systemic inflammation and bone homeostasis. In this study, we investigated the osteoprotective role of DCA in preclinical model of LPS-induced inflammatory bone loss. DCA supplementation improved bone mineral density, trabecular and cortical bone microarchitecture by suppressing osteoclastogenesis and enhancing osteoblastogenesis, indicating its dual regulatory role in bone remodelling. Furthermore, DCA treatment strengthened gut barrier integrity, reversed dysbiosis, and reduced systemic inflammation by balancing the pro-inflammatory (IL-17, TNF-α, IL-6, RANKL, etc.) and anti-inflammatory cytokines (IL-2, IL-4, TGF-β, IL-10). In line with these effects, the anti-resorptive effects of DCA were mediated through bile acid receptors TGR5 and FXR, as pharmacological inhibition of these receptors reversed DCA-induced suppression of osteoclastogenesis. Collectively, these findings demonstrate that DCA mitigates LPS-induced inflammatory bone loss through a multifaceted mechanism involving both direct effects on bone cells and restoration of gut integrity and homeostasis. This study highlights the therapeutic potential of targeting gut microbiota-derived bile acid pathways, particularly DCA, as a novel strategy for managing osteoporosis and other inflammatory bone disorders via modulating the “Gut-Bone” homeostasis.